Liquid dosage forms to treat cancer

ABSTRACT

This invention relates to a liquid pharmaceutical composition comprising cabozantinib to treat locally advanced or metastatic solid tumors, particularly advanced urothelial cancer or renal cell carcinoma in patients in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a United States National Phase filing of PCT/US2018/036703, filed Jun. 8, 2018, which claims the benefit of priority to U.S. Provisional Application No. 62/517,736, filed Jun. 9, 2017, and priority to 62/520,768, filed Jun. 16, 2017, the entire contents of which are incorporated herein by reference.

FIELD OF INVENTION

This invention relates to a liquid pharmaceutical formulation comprising an L-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

BACKGROUND OF THE INVENTION

Multi-targeted tyrosine kinase inhibitors (TKIs) chemotherapeutics have been instrumental in the recent advancements of anticancer treatment over the past several years. Tyrosine kinase inhibitor therapies have demonstrated broad clinical effects leading to new approved treatment options across multiple tumor types including renal cell carcinoma (RCC), urothelial carcinoma (UC), melanoma, non-small-cell lung cancer (NSCLC), and others. The success of this therapy type as a single agent has naturally led to interest in evaluating novel formulations that provide enhanced pharmacokinetics (PK) and pharmacodynamics (PD) of TKIs when used in combination with checkpoint inhibitors in search of further, possibly synergistic, anticancer clinical effects.

Medicaments, such as chemotherapeutic drugs that are administered orally, are dispensed to the patient in several dosage forms, including liquid forms such as solutions, syrups, emulsions, and suspensions, and more commonly, in solid forms such as capsules, caplets, and tablets. Children, older persons, and many other persons (including disabled or incapacitated patients) often have trouble swallowing tablets or capsules. In these situations, it is desirable to provide the drug either in a chewable solid form or a liquid form. Pharmaceutically active agents administered in solid dosage form are usually intended to be swallowed whole. In some cases, the unpleasant taste of the medicament in solid form is generally not of concern when formulating oral solid dosage forms, because the pharmaceutical's taste can be easily masked with an exterior coating.

However, despite the convenience of formulating medicaments in oral solid forms, for pediatric and geriatric patients, a liquid oral dosage form is preferred over a chewable dosage form. A liquid dosage form is especially preferred for pediatric and geriatric patients because of the ease with which it may be swallowed. Additionally, patients may be more inclined to comply with their medication instruction if the dosages are easier to ingest, particularly for products administered in large doses, requiring several tablets at a time.

Some liquid pharmaceutical compositions formulated for use by pediatric or geriatric patients are prepared by grinding a tablet dosage form into a powder and mixing the powder with a diluent. Such a formulation may cause some of the drug to remain undissolved, thereby affecting the therapeutic dose of drug in the composition. In addition, the powder exposes the unpleasant tasting pharmaceutically active agent, which may result in a lack of compliance due to the unacceptable taste. It is readily understood that such compositions are impractical and may result in underdosing or poor compliance.

SUMMARY OF THE INVENTION

The problem underlying the present invention is to provide a liquid dosage form containing a compound of Formula I, or a pharmaceutically acceptable salt thereof, which does not show the above-described disadvantages of the known dosage forms. In particular, the pharmaceutical formulation should be stable over a long time period, as well as physiologically acceptable and pleasing for pediatric and geriatric patients. In some embodiments, the liquid formulations of the present invention find utility in the treatment of cancer, for example, for the treatment of a solid tumor in a patient in need thereof.

In some embodiments, the solid tumor is a locally advanced or a metastatic solid tumor.

In some embodiments, the present invention is directed to a liquid pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof:

or a liquid pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein:

-   -   R¹ is halo;     -   R² is halo; and     -   Q is CH or N.

In various embodiments, a single dose of the liquid pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, for example, compound 1, or a pharmaceutically acceptable salt thereof, provides an interpatient or intrapatient exposure variability of less than 30%, or less than 25%, or less than 20%, or less than 19%, or less than 18%, or less than 17%, or less than 16%, or less than 15%, or less than 14%, or less than 13%, or less than 12%, or less than 11%, or less than 10%. In various embodiments, the exposure is represented by a noncompartmental PK parameter selected from the group consisting of: AUC_(0-t), AUC₀₋₂₄, AUC₀₋₇₂, AUC_(0-inf), C_(max), t_(max), k_(el), and t_(1/2). In some embodiments, the liquid formulation of the present invention when dosed as a single dose provides an AUC_(0-t), AUC₀₋₂₄, AUC₀₋₇₂, AUC_(0-inf), or a C_(max) interpatient or intrapatient variability of less than 30%, or less than 25%, or less than 20%, or less than 19%, or less than 18%, or less than 17%, or less than 16%, or less than 15%, or less than 14%, or less than 13%, or less than 12%, or less than 11%, or less than 10%. In some embodiments, the liquid formulation of the present invention when dosed as a single dose provides an AUC_(0-t), AUC₀₋₂₄, AUC₀₋₇₂, AUC_(0-inf), or C_(max) interpatient or intrapatient variability of less than 30%, or less than 25%, or less than 20%, or less than 19%, or less than 18%, or less than 17%, or less than 16%, or less than 15%, or less than 14%, or less than 13%, or less than 12%, or less than 11%, or less than 10% relative to a tablet formulation containing a compound of formula I, or a pharmaceutically acceptable salt thereof, for example, compound 1, or a pharmaceutically acceptable salt thereof. In the above related embodiments, the single dose can include a single dose of about: 200 mg, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140 mg, 130 mg, 120 mg, 110 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, or 10 mg of a compound of formula I, or compound 1 which can be the (L)-malate salt (also referred to herein as the S-malate salt; S-malate salt and (L)-malate salt are used interchangeably herein) or the (D)-malate salt (also referred to as the R-malate salt; R-malate salt and (D)-malate salt are used interchangeably herein). In various embodiments, the above referenced single doses comprises cabozantinib. Cabozantinib is also referred to as XL184, and XL184 and cabozantinib are used interchangeably herein.

Another aspect is directed to a method of treating a locally advanced or metastatic solid tumor, comprising administering to a patient in need of such treatment a liquid pharmaceutical composition comprising compound 1:

or a pharmaceutically acceptable salt thereof or a liquid pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In some aspects, the locally advanced or a metastatic solid tumor may be advanced UC (urothelial carcinoma) or RCC (renal cell carcinoma).

In another aspect, the invention comprises a liquid pharmaceutical dosage form comprising a compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, such that each dose of the liquid pharmaceutical composition comprising compound 1, or a pharmaceutically acceptable salt thereof provides the patient an interpatient or intrapatient exposure (for example, AUC_(0-t), AUC₀₋₂₄, AUC_(0-inf), C_(max), or t_(max)) variability of less than 30%, or less than 25%, or less than 20%, or less than 19%, or less than 18%, or less than 17%, or less than 16%, or less than 15%, or less than 14%, or less than 13%, or less than 12%, or less than 11%, or less than 10% relative to a tablet formulation containing the same amount of compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a line graph of the mean (±SD) cumulative excretion of urine and feces total radioactivity following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C] XL184 to healthy male subjects (N=8).

FIG. 2 depicts a line graph of the mean (±SD) plasma total radioactivity in plasma and whole blood and XL184 concentration (by LC/MS/MS method) vs. time 0-648 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C] XL184 to healthy male subjects—linear axes (N=8)

FIG. 3 depicts a line graph of the mean (±SD) plasma total radioactivity in plasma and whole blood and XL184 concentration (by LC/MS/MS method) vs. time 0-120 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C] XL184 to healthy male subjects—linear axes (N=8)

FIG. 4 depicts a line graph of the mean (±SD) plasma total radioactivity in plasma and whole blood and XL184 concentration (by LC/MS/MS method) vs. time 0-648 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C] XL184 to healthy male subjects—semilogarithmic axes (N=8).

FIG. 5 depicts a line graph of the mean (±SD) plasma total radioactivity in plasma and whole blood and XL184 concentration (by LC/MS/MS method) vs. time 0-120 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C] XL184 to healthy male subjects—semilogarithmic axes (N=8).

FIG. 6 depicts a line graph of the mean (±SD) percentage of 14C radioactivity associated with erythrocytes in whole blood over time graph following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C] XL184 to healthy male subjects (N=8).

FIG. 7 depicts a line graph of the mean (±SD) plasma concentrations of XL184 and metabolites XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured by LC/MS/MS method vs. time 0-648 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C] XL184 to healthy male subjects—linear axes (N=⁸).

FIG. 8 depicts a line graph of the mean (±SD) plasma concentrations of XL184 and metabolites XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured by LC/MS/MS method vs. time 0-120 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C] XL184 to healthy male subjects—linear axes (N=⁸).

FIG. 9 depicts a line graph of the mean (±SD) plasma concentrations of XL184 and metabolites, XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured by LC/MS/MS method vs. time 0-648 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C] XL184 to healthy male subjects—semilogarithmic axes (N=8).

FIG. 10 depicts a line graph of the mean (±SD) plasma concentrations of XL184 and metabolites, XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured by LC/MS/MS method vs. time 0-120 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C] XL184 to healthy male subjects—semilogarithmic axes (N=8).

FIG. 11 depicts a line graph of the mean (±SD) plasma concentrations of demethyl half-dimer sulfate, P5, P7, XL-184, XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured by radio-quantitation method vs. time 0-336 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C]-XL184 to healthy male subjects—linear axes.

FIG. 12 depicts a line graph of the mean (±SD) plasma concentrations of demethyl half-dimer sulfate, P5, P7, XL-184, XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured by radio-quantitation method vs. time 0-80 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C]-XL184 to healthy male subjects—linear axes.

FIG. 13 depicts a line graph of the mean (±SD) plasma concentrations of demethyl half-dimer sulfate, P5, P7, XL-184, XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured by radio-quantitation method vs. time 0-336 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C]-XL184 to healthy male subjects—semilogarithmic axes.

FIG. 14 depicts a line graph of the mean (±SD) plasma concentrations of demethyl half-dimer sulfate, P5, P7, XL-184, XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured by radio-quantitation method vs. time 0-80 hours following a single 175 mg oral administration of XL184 (L-malate salt) containing 100 μCi [¹⁴C]-XL184 to healthy male subjects—semilogarithmic axes.

FIG. 15 depicts proposed major biotransformation products of XL184 (cabozantinib).

Definitions ADME Absorption, distribution, metabolism, and excretion AE Adverse event ALT (SGPT) Alanine aminotransferase (serum glutamic-pyruvate transaminase) Anti-HAV Hepatitis A total antibody Anti-HBc Hepatitis B core antigen antibody Anti-HBs Hepatitis B surface antigen antibody AST (SGOT) Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) AUC_(0-inf) Area under the concentration-time curve from time zero to infinity AUC₀₋₂₄ Area under the concentration-time curve from time zero to time 24 hours AUC₀₋₇₂ Area under the concentration-time curve from time zero to time 72 hours AUC_(0-t) Area under the concentration-time curve from time zero to time of the last measurable concentration BMI Body mass index BUN Blood urea nitrogen ° C. Degrees Celsius Chem Chemistry C_(max) Maximum observed concentration CTCAE Common Terminology Criteria for Adverse Events % CV Percentage coefficient of variation CYP Cytochrome P450 % Dose_((feces)) Percentage of dose recovered in feces over the collection interval % Dose_((urine)) Percentage of dose recovered in urine over the collection interval ECG Electrocardiogram eCRF Electronic case report form ETR Percentage of ¹⁴C radioactivity associated with erythrocytes in whole blood ° F. Degrees Fahrenheit g Gram GI Gastrointestinal GLP Good laboratory practice HBsAg Hepatitis B surface antigen HCV Hepatitis C antibodies Hem Hematology HIV Human immunodeficiency virus ICF Informed consent form ICH International Conference on Harmonization IGm Immunoglobulin M INN International Nonproprietary Name LLOQ Lower limit of quantification IRB Institutional Review Board k_(el) Apparent terminal elimination rate constant kg Kilogram LC-MS/MS Liquid chromatography-mass spectrometry/mass spectrometry m Meter MBq Megabecquerel MedDRA ® Medical Dictionary for Regulatory Activities MET Hepatocyte growth factor receptor protein mg Milligram μCi Microcurie mL Milliliter mmHg Micrometers of mercury msec millisecond MTD Maximum tolerated dose NA Not applicable NCI National Cancer Institute NE Not estimated ng Nanogram ngEq An equivalent amount of XL184 freebase required to produce a measured or calculated amount of total radioactivity NR Not reportable p-FA Para-fluoroaniline PK Pharmacokinetic PO Oral QTc Corrected QT interval RBC Red blood cell RET Rearranged during transfection SAE Serious adverse event SAP Statistical analysis plan SD Standard deviation SOP Standard operating procedure TEAE Treatment-emergent adverse event t_(max) Time of maximum concentration t_(1/2) Apparent terminal elimination half-life calculated as ln(2)/k_(e1) UPCr Urine Protein/Creatinine ratio US United States of America USAN United States Adopted Name VEGFR2 Vascular endothelial growth factor receptor 2 WBC White blood cell WHO World Health Organization XL184 The product number used by Exelixis for development of the compound with the USAN/INN designation of cabozantinib

DETAILED DESCRIPTION

As indicated above, the invention is directed to a method of treating a locally advanced or a metastatic solid tumor, comprising administering a liquid formulation of a compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof.

Compound 1 is known by its chemical name N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and by the name cabozantinib (also referred to as XL184). COMETRIQ™ (Cabozantanib S-Malate oral capsules) has been approved by the Food and Drug Administration (FDA) in the United States on Nov. 29, 2012, for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). CABOMETYX™ (Cabozantanib S-Malate oral tablets) has been approved by the Food and Drug Administration (FDA) in the United States on Apr. 25, 2016, for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. Cabozantinib is formulated as the L-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. WO 2005/030140, the entire contents of which is incorporated herein by reference, discloses compound, describes how it is made (Example 48), and discloses the therapeutic activity of this compound to inhibit, regulate, and/or modulate the signal transduction of kinases (Assays, Table 4, entry 289). Example 48 begins at paragraph [0353] in WO 2005/030140. Information for compound 1 is available from the FDA at http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=208692 (last visited Dec. 19, 2016) and is incorporated herein by reference in its entirety.

In various embodiments, the present invention provides a pharmaceutical composition formulated for oral administration in liquid form. When compared to solid forms, for example, a formulation in tablet, capsule, sachet, or powdered form, the liquid pharmaceutical compositions of the present invention comprising a compound of formula I or compound 1, which can be the (L)-malate salt or the (D)-malate salt, provides a significantly smaller interpatient or intrapatient variability in exposure. For example, as published in Nguyen, L. et al., “Pharmacokinetics of cabozantinib tablet and capsule formulations in healthy adults,” (2016), Anti-Cancer Drugs 2016, 27:669-678, (the disclosure of which is incorporated herein by reference in its entirety), the values of C_(max), AUC_(0-t), and AUC_(0-inf) plasma pharmacokinetic parameters were highly variable among study participants, ranging from (i.e. % CV about 48-72%, 42-56%, and 38-41% for the 20, 40, and 60 mg (free base equivalent, FBE) cabozantinib tablet strength treatments, respectively). Table 1 (reproduced from the Nguyen, L. et al., reference cited herein) summarizes the plasma PK parameters found when healthy patients were dosed with a single dose of 140 mg (free base equivalent, FBE) of cabozantinib or the malate salt of compound 1. The values of C_(max), AUC_(0-t), and AUC_(0-inf) plasma pharmacokinetic parameters were highly variable among study participants (i.e. % CV about 54%, 44%, 46% and 43%, 37%, and 39% for the 140 mg (free base equivalent, FBE) cabozantinib tablet and capsule dose treatments, respectively).

TABLE 1 Summary of cabozantinib plasma pharmacokinetic parameters from healthy individuals administered a single oral dose of tablet or capsule formulations containing 140 mg of cabozantinib (free base equivalent, FBE). Pharmacokinetic Tablet treatment Capsule treatment parameter (mean ± CV %)^(a) (mean ± CV %)^(b) C_(max) (ng/ml) 702 ± 54 554 ± 43 t_(max) (h)^(c) 3.49 (1.99, 24.00) 4.00 (2.00, 5.04) AUC_(0-t) (ng × h/ml) 61 900 ± 44   54 900 ± 37   AUC_(0-inf) (ng × h/ml) 65 800 ± 46   58 300 ± 39   t_(1/2) (h) 115 ± 31 112 ± 26 CL/F (l/h) 2.61 ± 49  2.69 ± 32  VZ/F (l) 424 ± 58 426 ± 37 AUC, area under the plasma concentration-time curve; CL/F, oral clearance; CV, coefficient of variation. ^(a)Treatment A (test): 140 mg dose (2 × 20 + 1 × 100 mg) of XL184 (cabozantinib) tablet formulation; (n = 72). ^(b)Treatment B (reference): 140 mg dose (3 × 20 + 1 × 80 mg) of XL184 (cabozantinib) capsule formulation; (n = 72). ^(c)Median (minimum, maximum) are presented.

In these and other embodiments, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered as a liquid pharmaceutical composition, wherein the liquid pharmaceutical composition additionally comprises a pharmaceutically acceptable carrier, excipient, or diluent. In a specific embodiment, the compound of formula I is compound 1, or a pharmaceutically acceptable salt thereof.

The compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof as described herein, includes both the recited compounds as well as individual isomers and mixtures of isomers. In each instance, the compound of formula I includes the pharmaceutically acceptable salts, hydrates, and/or solvates of the recited compounds and any individual isomers or mixture of isomers thereof.

In other embodiments, the compound of formula I or compound 1 can be the (L)-malate salt (also referred to herein as the S-malate salt), or the (D)-malate salt (also referred to as the R-malate salt). The malate salt of the compound of formula I and of compound 1 is disclosed in PCT/US2010/021194 and U.S. Patent Application Ser. No. 61/325,095, the entire contents of each of which are incorporated herein by reference.

In other embodiments, the compound of formula I can be malate salt.

In other embodiments, the compound of formula I can be the (D)-malate salt.

In other embodiments, the compound of formula I can be the (L)-malate salt.

In other embodiments, compound 1 can be the malate salt.

In other embodiments, compound 1 can be (D)-malate salt.

In other embodiments, compound 1 can be the (L)-malate salt.

In another embodiment, the malate salt is in the crystalline N-1 form of the (L) malate salt and/or the (D) malate salt of the compound 1 as disclosed in U.S. Patent Application Ser. No. 61/325,095. In another embodiment, the malate salt is the crystalline N-2 form of the (L) malate salt and/or the (D) malate salt of the compound 1 as disclosed in U.S. Patent Application Ser. No. 61/325,095. In yet another embodiment, the malate salt is a mixture of the N-1 and N-2 forms of the (L) malate salt and/or the (D) malate salt of the compound 1 as disclosed in U.S. Patent Application Ser. No. 61/325,095. See also WO 2008/083319 for the properties of crystalline enantiomers, including the N-2 crystalline forms of the (L)-malate salt (also referred to as the S-malate salt) or the (D)-malate salt (also referred to as the R-malate salt), and/or the N-1 crystalline forms of the (L)-malate salt (also referred to as the S-malate salt) or the (D)-malate salt (also referred to as the R-malate salt) of compound 1. Methods of making and characterizing such forms are fully described in PCT/US10/21194, which is incorporated herein by reference in its entirety.

In one embodiment, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In a further embodiment, a compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered with fasting (i.e., without eating) for approximately two hours before and 1 hour after administration.

In another embodiment, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered orally once daily as a liquid formulation.

In another embodiment, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered orally as its free base or malate salt as a liquid formulation.

In various embodiments, a single dose of the liquid pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, for example, compound 1, or a pharmaceutically acceptable salt thereof, provides an interpatient or intrapatient exposure variability of less than 30%, or less than 25%, or less than 20%, or less than 19%, or less than 18%, or less than 17%, or less than 16%, or less than 15%, or less than 14%, or less than 13%, or less than 12%, or less than 11%, or less than 10%. In various embodiments, the exposure is represented by a noncompartmental PK parameter selected from the group consisting of: AUC_(0-t), AUC₀₋₂₄, AUC₀₋₇₂, AUC_(0-inf), C_(max), t_(max), k_(el), and t_(1/2). In some embodiments, the liquid formulation of the present invention when dosed as a single dose provides an AUC_(0-t), AUC₀₋₂₄, AUC₀₋₇₂, AUC_(0-inf), or a C_(max) interpatient or intrapatient variability of less than 30%, or less than 25%, or less than 20%, or less than 19%, or less than 18%, or less than 17%, or less than 16%, or less than 15%, or less than 14%, or less than 13%, or less than 12%, or less than 11%, or less than 10%. In some embodiments, the liquid formulation of the present invention when dosed as a single dose provides an AUC_(0-t), AUC₀₋₂₄, AUC₀₋₇₂, AUC_(0-inf), or C_(max) interpatient or intrapatient variability of less than 30%, or less than 25%, or less than 20%, or less than 19%, or less than 18%, or less than 17%, or less than 16%, or less than 15%, or less than 14%, or less than 13%, or less than 12%, or less than 11%, or less than 10% relative to a tablet formulation containing a compound of formula I, or a pharmaceutically acceptable salt thereof, for example, compound 1, or a pharmaceutically acceptable salt thereof.

In the above related embodiments, the single dose can include a single dose of about: 200 mg, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140 mg, 130 mg, 120 mg, 110 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, or 10 mg of a compound of formula I or compound 1, which can be the (L)-malate salt (also referred to herein as the S-malate salt) or the (D)-malate salt (also referred to as the R-malate salt). In various embodiments, the above referenced single doses comprises cabozantinib.

The amounts of the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, that are administered will vary. In one embodiment, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of from about 1 mg to about 200 mg, or from about 5 mg to about 175 mg, or from about 10 mg to about 100 mg, for example, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140, mg, 130 mg, 120 mg, 110 mg, 100 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, or 15 mg, within a fixed liquid dosage volume, for example, in a volume of about 1.0 mL to about 100 mL, or for example from about 10 mL to about 100 mL per unit dose. In another embodiment, the amount of the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140, mg, 130 mg, 120 mg, 110 mg, 100 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, or 15 mg per unit volume (equivalent to a daily dose or a unit dose, or some fraction or part thereof) ranging from about 1 mL to about 100 mL, or from about 10 mL to about 100 mL per dose. In another embodiment, the amount of the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 140 mg, about 80 mg, about 60 mg, about 40 mg, or about 20 mg per unit volume (equivalent to a daily dose or a unit dose, or some fraction or part thereof) ranging from about 1 mL to about 100 mL, or from about 10 mL to about 100 mL per unit dose. In another embodiment, the amount of the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered in a volume ranging from about 1 mL to about 100 mL, or from about 10 mL to about 100 mL per dose (equivalent to a daily dose, or a unit dose, or some fraction or part thereof), wherein each dose contains about 60 mg, or about 40 mg, or about 20 mg of the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, for example, an (L)-malate salt (also referred to as the S-malate salt) or the (D)-malate salt (also referred to as the R-malate salt), and/or the N-1 crystalline forms of the (L)-malate salt (also referred to as the S-malate salt) or the (D)-malate salt (also referred to as the R-malate salt) of compound 1.

In these and other embodiments, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered orally once daily as its free base or as the malate salt as a liquid dosage form, preferably in a daily dose, or a unit dose, or some fraction or part thereof. In a further embodiment, compound 1 is administered as the (L)-malate salt (also referred to as the S-malate salt) or the (D)-malate salt (also referred to as the R-malate salt). In a further embodiment:

-   -   up to and including 150 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 140 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 130 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 120 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 110 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 100 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 95 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 90 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 85 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 80 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 75 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 70 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 65 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 60 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 55 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 50 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 45 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 40 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 35 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 30 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 25 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 20 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 15 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 10 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered; or     -   up to and including 5 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered.     -   In each of the aforementioned examples, the amount of compound 1         or a pharmaceutically acceptable salt thereof is admixed with         one or more carriers to prepare an oral formulation containing,         for example, from about 50% to about 95% PEG-400 (w/w), and/or         from about 1% to about 30% TPGS (w/w), and/or from about 0.5% to         about 20% ethanol (w/w). In each of the aforementioned examples,         the amount of compound 1 or a pharmaceutically acceptable salt         thereof is admixed with one or more carriers to prepare an oral         formulation containing, for example, from about 70% to about 90%         PEG-400 (w/w), and/or from about 5% to about 20% TPGS (w/w),         and/or from about 1% to about 15% ethanol (w/w).     -   In each of the aforementioned examples, the amount of compound 1         or a pharmaceutically acceptable salt thereof is admixed with         one or more carriers to prepare an oral formulation containing,         for example, from about 80% to about 90% PEG-400 (w/w), and/or         from about 5% to about 15% TPGS (w/w), and/or from about 1% to         about 10% ethanol (w/w).     -   In each of the aforementioned examples, the amount of compound 1         or a pharmaceutically acceptable salt thereof is admixed with         one or more carriers to prepare an oral formulation containing,         for example, about 85% PEG-400 (w/w), and/or about 10% TPGS         (w/w), and/or about 5% ethanol (w/w).

In these and other embodiments, a liquid formulation comprising compound 1 which is administered orally once daily with fasting as its free base or as a malate salt (for example, the (L)-malate salt, which is also referred to as the S-malate salt, or the (D)-malate salt, which is also referred to as the R-malate salt) to a patient in need thereof. In a further embodiment:

-   -   up to and including 150 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 140 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 130 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 120 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 110 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 100 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 95 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 90 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 85 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 80 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 75 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 70 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 65 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 60 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 55 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 50 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 45 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 40 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 35 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 30 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 25 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 20 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 15 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered;     -   up to and including 10 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered; or     -   up to and including 5 mg of compound 1 or a pharmaceutically         acceptable salt thereof is administered,     -   In each of the aforementioned examples, the amount of compound 1         or a pharmaceutically acceptable salt thereof is admixed with         one or more carriers to prepare an oral formulation containing,         for example, from about 50% to about 95% PEG-400 (w/w), and/or         from about 1% to about 30% TPGS (w/w), and/or from about 0.5% to         about 20% ethanol (w/w).     -   In each of the aforementioned examples, the amount of compound 1         or a pharmaceutically acceptable salt thereof is admixed with         one or more carriers to prepare an oral formulation containing,         for example, from about 70% to about 90% PEG-400 (w/w), and/or         from about 5% to about 20% TPGS (w/w), and/or from about 1% to         about 15% ethanol (w/w).     -   In each of the aforementioned examples, the amount of compound 1         or a pharmaceutically acceptable salt thereof is admixed with         one or more carriers to prepare an oral formulation containing,         for example, from about 80% to about 90% PEG-400 (w/w), and/or         from about 5% to about 15% TPGS (w/w), and/or from about 1% to         about 10% ethanol (w/w).     -   In each of the aforementioned examples, the amount of compound 1         or a pharmaceutically acceptable salt thereof is admixed with         one or more carriers to prepare an oral formulation containing,         for example, about 85% PEG-400 (w/w), and/or about 10% TPGS         (w/w), and/or about 5% ethanol (w/w).

In various embodiments, a patient with a solid tumor, for example, a locally advanced or metastatic solid tumor, may be treated with compound 1, or a pharmaceutically acceptable salt thereof, as a liquid formulation containing 140 mg, 80 mg, 60 mg, 40 mg, or 20 mg of compound 1, which is administered orally once daily with fasting as its free base or as a malate salt (for example, the (L)-malate salt, which is also referred to as the S-malate salt, or the (D)-malate salt, which is also referred to as the R-malate salt).

In various embodiments, a patient with a solid tumor, for example, a locally advanced or metastatic solid tumor, may be treated with cabozantinib (S)-malate, which is administered orally once daily with fasting as a liquid dosage form comprising cabozantinib (S)-malate.

In a further embodiment, the cabozantinib (S)-malate is administered in a liquid pharmaceutical composition formulation containing 140 mg, 80 mg, 60 mg, 40 mg, or 20 mg of cabozantinib orally once daily with fasting. In a further embodiment, as shown in Table 1, the cabozantinib (S)-malate is administered in a liquid pharmaceutical composition which comprises one or more excipients, carriers, or diluents. Depending on the type of pharmaceutical composition, the pharmaceutically acceptable carrier may be chosen from any one or a combination of carriers known in the art. The choice of the pharmaceutically acceptable carrier depends partly upon the desired method of administration to be used. For a pharmaceutical composition of this disclosure, that is, one of the active compound(s) or a crystalline form of one of the active compound(s) of formula I or compound 1, a carrier should be chosen so as to substantially maintain the particular form of the active compound(s), whether it is crystalline or not. In other words, the carrier should not substantially alter the form of the active compound(s), nor should the carrier be otherwise incompatible with the form of the active compound(s), such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition. Various carriers used in formulating pharmaceutically acceptable compositions and known techniques for their bulk preparation and subsequent production into unit dosage forms are employed to make the pharmaceutical compositions disclosed herein and are described in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York. The amount of carriers and excipients used in a composition can be varied proportionally according to the amount of active ingredient used (that is, a compound of formula I or compound I, or a pharmaceutically acceptable salt thereof). For example, in each of the aforementioned examples, the amount of compound 1 or a pharmaceutically acceptable salt thereof is admixed with one or more carriers to prepare an oral formulation containing, for example, from about 50% to about 95% PEG-400 (w/w), and/or from about 1% to about 30% TPGS (w/w), and/or from about 0.5% to about 20% ethanol (w/w).

-   -   In each of the aforementioned examples, the amount of compound 1         or a pharmaceutically acceptable salt thereof is admixed with         one or more carriers to prepare an oral formulation containing,         for example, from about 70% to about 90% PEG-400 (w/w), and/or         from about 5% to about 20% TPGS (w/w), and/or from about 1% to         about 15% ethanol (w/w).     -   In each of the aforementioned examples, the amount of compound 1         or a pharmaceutically acceptable salt thereof is admixed with         one or more carriers to prepare an oral formulation containing,         for example, from about 80% to about 90% PEG-400 (w/w), and/or         from about 5% to about 15% TPGS (w/w), and/or from about 1% to         about 10% ethanol (w/w).     -   In each of the aforementioned examples, the amount of compound 1         or a pharmaceutically acceptable salt thereof is admixed with         one or more carriers to prepare an oral formulation containing,         for example, about 85% PEG-400 (w/w), and/or about 10% TPGS         (w/w), and/or about 5% ethanol (w/w).

Suitable carriers include, but are not limited to, water, saline, aqueous dextrose, glycerol, ethanol, and the like; solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, and dimethylformamide; oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.

The liquid pharmaceutical compositions of this disclosure may be prepared by methods know in the pharmaceutical formulation art, for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990).

Pharmaceutically acceptable adjuvants known in the pharmaceutical formulation art may also be used in the pharmaceutical compositions of this disclosure. These include, but are not limited to, preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. If desired, a pharmaceutical composition of this disclosure may also contain minor amounts of auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and antioxidants, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, and butylated hydroxytoluene. The pharmaceutical compositions generally contain about 0.5% to about 99.5% by weight of the active compound(s), or a crystalline form of the active compound(s), and 99.5% to 0.5% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 1% and about 75% by weight of active compound, with the rest being suitable pharmaceutical excipients or other adjuvants, as discussed herein.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., one or more compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, polyethylene glycol (PEG), ethanol, and the like; and further comprising solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.

Suspensions, in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

TABLE 2 An example of a liquid formulation containing cabozantinib (S)-malate. Theoretical Quantity (mg/unit dose) 20-mg 40-mg 60-mg Ingredient Dose Dose Dose Cabozantinib (S)-malate 25.34 50.68 76.02 Polyethylene glycol 400 (PEG 400) 2,934.88 5,869.77 8,804.65 d-α-tocopheryl polyethylene 345.28 690.56 1,035.84 glycol succinate (TPGS) Ethanol 172.64 345.28 517.92 Flavorings 3.45 6.91 10.36 Total 3,481.60 6,963.19 10,444.79

In a further embodiment, the cabozantinib (S)-malate is administered orally once daily.

In a further embodiment, the amount of cabozantinib (S)-malate that is administered orally once daily is 140 mg.

In a further embodiment, the amount of cabozantinib (S)-malate that is administered orally once daily is 120 mg.

In a further embodiment, the amount of cabozantinib (S)-malate that is administered orally once daily is 80 mg.

In a further embodiment, the amount of cabozantinib (S)-malate that is administered orally once daily is 60 mg.

In a further embodiment, the amount of cabozantinib (S)-malate that is administered orally once daily is 40 mg.

In a further embodiment, the amount of cabozantinib (S)-malate that is administered orally once daily is 20 mg.

In a further embodiment, the cabozantinib (R)-malate is administered orally once daily.

In a further embodiment, the amount of cabozantinib (R)-malate that is administered orally once daily is 140 mg.

In a further embodiment, the amount of cabozantinib (R)-malate that is administered orally once daily is 120 mg.

In a further embodiment, the amount of cabozantinib (R)-malate that is administered orally once daily is 80 mg.

In a further embodiment, the amount of cabozantinib (R)-malate that is administered orally once daily is 60 mg.

In a further embodiment, the amount of cabozantinib (R)-malate that is administered orally once daily is 40 mg.

In a further embodiment, the amount of cabozantinib (R)-malate that is administered orally once daily is 20 mg.

In another embodiment, compound 1 is administered orally as its free base or a malate salt (for example, the (L)-malate salt, which is also referred to as the S-malate salt, or the (D)-malate salt, which is also referred to as the R-malate salt) once daily in a liquid pharmaceutical composition as provided in the following Table 3.

TABLE 3 An example of a liquid formulation containing cabozantinib (S)-malate. Ingredient (% w/w) Compound 1 0.73 Polyethylene glycol 400 (PEG 400) 84.30 d-α-tocopheryl polyethylene 9.92 glycol succinate (TPGS) Ethanol 4.96 Flavorings 0.10 Total 100

In another embodiment, compound 1 is administered orally as its free base or a malate salt ((L)-malate salt (also referred to as the S-malate salt), or the (D)-malate salt (also referred to as the R-malate salt)) once daily in a liquid pharmaceutical composition as provided in the following table 4.

TABLE 4 An example of a liquid formulation containing cabozantinib (S)-malate. Theoretical Quantity Ingredient (mg/unit dose) Compound 1 175.00 Polyethylene glycol 400 (PEG 400) 20,268.53 d-α-tocopheryl polyethylene 2,384.53 glycol succinate (TPGS) Ethanol 1,192.27 Flavorings 23.85 Total 24,044.18

In another embodiment, compound 1 is administered orally as its free base or a malate salt ((L)-malate salt (also referred to as the S-malate salt), or the (D)-malate salt (also referred to as the R-malate salt)) once daily as a liquid dose as provided in the following table 5.

TABLE 5 An example of a liquid formulation containing cabozantinib (S)-malate. Ingredient Function % w/w Cabozantinib (S)-malate Active Ingredient 0.73 Polyethylene glycol 400 (PEG 400) Solubility Enhancer 84.30 d-α-tocopheryl polyethylene glycol Solubility Enchancer 9.92 succinate (TPGS) and Stabilizer Ethanol Solvent 4.96 Cinnamon Flavoring Taste masking agent 0.10 Total 100

Any of the liquid dosage formulations provided above can be adjusted according to the dose of compound 1 or a pharmaceutically acceptable salt thereof desired. Thus, the amount of each of the formulation ingredients can be proportionally adjusted to provide a liquid formulation containing various amounts of compound 1 or a pharmaceutically acceptable salt thereof as provided in the previous paragraphs. In another embodiment, the formulations can contain 20, 40, 60, or 80 mg of compound 1 or a pharmaceutically acceptable salt thereof.

Exemplary Administration of the Liquid Pharmaceutical Composition and Treatment of Solid Tumors

Through potent inhibition of RTKs including MET, VEGFR, and AXL, cabozantinib has demonstrated clinical activity as a single agent in both advanced UC and RCC.

Objectives: The primary objectives of the study were: (1) to determine the time course for excretion of ¹⁴C radioactivity in urine and feces following a single 175 mg oral dose of XL184 (L-malate salt) containing 100 μCi [14C]-XL184; (2) to determine the recovery of ¹⁴C radioactivity as a percentage of the administered dose; (3) to determine the percentage of ¹⁴C radioactivity present as XL184 in plasma and urine at selected time points following administration of the study drug; and (4) to assess the safety of a single dose of 175 mg of XL184 (L-malate salt) containing 100 μCi [¹⁴C]-XL184 in healthy male subjects. The secondary objectives of the study were: (1) to determine the plasma pharmacokinetics of ¹⁴C radioactivity and XL184 in healthy male subjects following a single oral dose of study drug; (2) to determine the percentage of ¹⁴C radioactivity associated with erythrocytes in whole blood over time; and (3) to estimate the amount and probable structure of any significant metabolites or degradation products of XL184 in plasma and urine.

The following PK objectives listed above will not be addressed in this example:

Primary objective (3): to determine the percentage of ¹⁴C radioactivity present as XL184 in plasma and urine at selected time points following administration of the study drug;

Secondary objective (3): to estimate the amount and probable structure of any significant metabolites or degradation products of XL184 in plasma and urine.

The study was completed as planned.

Methodology: This was an open-label, single-dose, single-center, mass balance, Phase 1 study in healthy male volunteers. There were two study periods: a Screening Period, during which subjects underwent assessments to determine their eligibility for the study, and an On-study Period, which started on Day-1 (‘check-in’ day) when the subject was admitted to the Celerion clinic. Subjects received a single calculated oral dose intended to contain a total of 175 mg of XL184 (L-malate salt) and 100 μCi of ¹⁴C at Hour 0 on Day 1; initially they were to remain in the clinic through to the completion of all scheduled post-dose procedures on the morning of Day 28. Alternatively, if scintillation counts were available, subjects, on an individual basis, could be discharged prior to Day 28 if either of the following conditions were met: (1) ≥90% of the administered radioactivity was recovered in the urine and feces (accounting for radioactivity in vomitus if applicable); or (2) the daily total excreted radioactivity was 1% or less of the administered dose on 2 consecutive days and ≥85% of the administered radioactivity had been recovered. However, subjects who were discharged from the clinic before Day 28 were required to return to the clinic for all remaining scheduled pharmacokinetic blood sampling and the Day 28 safety assessments. Subjects not meeting radioactivity release criteria by Day 28 could be asked to remain confined in the clinic or continue collection of urine and feces at home (returning samples to the clinic daily) for up to an additional 7 days (through to Day 35). Due to the fact that by Day 35 subjects had still not met release criteria, subjects were given the option of withdrawing from the study or completing the additional 14-day collection period (either in the clinic or as a daily visitor) with urine and feces collections and daily adverse event (AE) inquiries. All urine and fecal collections for all subjects stopped following the conclusion of the Day 49 scheduled events regardless of percentage of total radioactive dose recovered.

Number of subjects (planned and analyzed): 8 planned and 8 analyzed

Diagnosis and main criteria for eligibility: Healthy male adults, aged 19 to 55 years of age, with screening and check in amylase or lipase levels below the upper limit of normal, a minimum of one bowel movement a day, and no evidence of urinary obstruction or difficulty in voiding urine at screening.

Test product, dose and mode of administration, and batch numbers: XL184 (L-malate salt) containing [¹⁴C]-XL184 (100 μCi dose) was prepared as a dosing solution. Each dosing solution was analyzed for radioactivity content (scintillation counting), radiochemical purity, and XL184 concentration. A single dose oral solution was administered at Hour 0 on Day 1 by the clinic staff. The dose was given via the scintillation vial. Following dosing, the scintillation vial was rinsed 3 times with room temperature distilled water, and the rinsate was administered to the subject. Residual radioactivity was determined for each dosing vial. The total volume of liquid administered including radiolabelled study drug, rinses, and water given for dosing (in addition to the rinses) was the same for each subject.

Duration of treatment: Each subject was dosed with a single 175 mg oral solution dose of XL184 (L-malate salt) containing [¹⁴C]-XL184 (100 μCi).

Reference therapy, dose and mode of administration, and batch numbers: Not applicable.

Criteria for Evaluation:

Efficacy: Not applicable (efficacy was not measured in this study)

Pharmacokinetics: Serial blood, urine, and feces were collected at specified times following dosing. As data allowed, standard noncompartmental pharmacokinetic parameters, including area under the concentration-time curve calculated using linear trapezoidal summation from time zero to time t, where t is the time of the last measurable concentration (AUC0-t), area under the concentration-time curve calculated using linear trapezoidal summation from time zero to time 24 hours (AUC₀₋₂₄), area under the concentration-time curve calculated using linear trapezoidal summation from time zero to time 72 hours (AUC₀₋₇₂), area under the concentration-time curve from time zero to infinity, AUC_(0-inf)=AUC_(0-t)+Ct/kel, where kel is the terminal elimination rate constant and C_(t) is the last measurable concentration (AUC_(0-inf)), maximum observed concentration (C_(max)), time of maximum concentration (t_(max)), apparent terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration vs. time curve (k_(el)), and apparent terminal elimination half-life calculated as ln(2)/k_(el)(t_(1/2)) were calculated from radioactivity data in plasma and whole blood, and standard noncompartmental pharmacokinetic parameters, including AUC_(0-t), AUC₀₋₂₄, AUC_(0-inf), C_(max), t_(max), k_(el), and t_(1/2), were calculated from XL184 and/or metabolite concentrations in plasma.

As data allowed, pharmacokinetic parameters, including urine concentration (Curine), amount excreted during each collection interval, calculated as C_(urine)×urine volume, renal clearance, cumulative amount of dose excreted in urine, percentage recovered in urine over the collection interval, and cumulative percent of dose recovered in urine, were calculated from XL184 and metabolites concentrations in urine. Fecal concentration (C_(feces)), amount excreted during each collection interval, calculated as C_(feces)×fecal weight, cumulative amount of dose excreted in feces, percentage of dose recovered in feces over the collection interval, and cumulative percent of dose recovered in feces, were also calculated from XL184 and metabolites concentrations in feces.

Mass balance was calculated as the percent of total administered radioactivity recovered in urine and feces. For the purpose of calculating mass balance, the amount of administered radioactivity was defined as the total radioactivity in the dosing solution minus any radioactivity lost due to emesis (if any occurred), adsorption to the dosing vial, etc.

To determine the percentage of radioactivity associated with erythrocytes in whole blood over time (ETR; calculated only for time points that whole blood is collected), the following was calculated:

The amount of ¹⁴C radioactivity in plasma versus whole blood, adjusted for the hematocrit, at the specific time points of comparison (ETR=Xe/Xb=1−[Cp*(1−Hct)/Cb], where Xe and Xb stands for amount of radioactivity in erythrocyte or whole blood, respectively. Hematocrit values for Days-1, 2, and 4 were averaged for use in this calculation.

Safety: Safety evaluations included assessments of AEs, vital signs, electrocardiogram (ECG), laboratory tests, and concomitant medications. Adverse event seriousness, severity grade, and relationship to study treatment were assessed by the investigator. Severity grade was defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Adverse event terms were standardized using the Medical Dictionary for Regulatory Activities and tabulated by system organ class and preferred term.

Metabolic Profiling: Details regarding metabolic profiling were prepared under separate cover by QPS, LLC. The results will be reported separately.

Statistical Methods:

Efficacy: Not applicable (efficacy was not measured in this study).

Pharmacokinetics: The pharmacokinetic parameters identified above were summarized using descriptive statistics (e.g., mean, median, standard deviation [SD], coefficient of variation (CV), standard error of the mean, geometric mean, minimum, maximum, and sample size). No inferential statistics were calculated. The radiocarbon concentration over each collection period was determined for plasma, whole blood, urine, and feces. To determine the percentage of radioactivity associated with erythrocytes in whole blood over time (calculated only for time points that whole blood is collected) the following was calculated: the amount of radioactivity in plasma versus whole blood, adjusted for the hematocrit, at the specific time points of comparison (ETR=Xe/Xb=1−[Cp*(1−Hct)/Cb], where Xe and Xb stands for amount of radioactivity in erythrocyte or whole blood, respectively. Hematocrit values for Days-1, 2, and 4 were averaged for use in this calculation.

Safety: AEs and other safety data were summarized and listed as appropriate. Laboratory values were presented to allow evaluation of changes after baseline. No safety data were formally analyzed.

No interim analyses were performed.

Summary of Results:

Disposition of Subjects:

Eight subjects were dosed; one subject was followed for 37 days then withdrew consent while seven subjects were followed for 49 days for urine and feces collection, and one of the seven opted for home collection for the final 14 day extension.

Pharmacokinetic Results:

Radioactivity Recovery

A summary of cumulative recovery of total radioactivity (as percent of dose) in the urine and feces following a single 175 mg oral administration of XL184 (L-malate salt) containing [¹⁴C]XL184 (100 μCi) to the healthy male subjects is presented in the following table.

Summary (mean±SD and % CV) of cumulative recovery of total radioactivity (as percent of dose) in urine and feces following a single 175 mg oral administration of XL184 (L-malate salt) containing [¹⁴C]XL184 (100 μCi) to healthy male subjects as shown below in Table 6.

TABLE 6 Cumulative recovery of total radioactivity. Cumulative Recovery of Total Radioactivity (as Percent of Dose) (n = 8) Urine Feces Total 27.29 ± 4.65 (17%) 53.79 ± 4.52 (8%) 81.09 ± 1.56 (2%)

The mean recovery of radioactivity of 81.09% was achieved within 48 days, and the radioactivity was mainly eliminated in feces (53.79%) and the remainder in urine (27.29%). Less than 1% total mean radioactivity was recovered in feces and urine after Day 28 post dose.

Radioactivity in Plasma and Whole Blood

A summary of plasma and whole blood pharmacokinetic parameters for total radioactivity following a single 175 mg oral administration of XL184 (L-malate salt) containing [¹⁴C]XL184 (100 μCi)) to healthy male subjects is presented in the following table.

Summary (mean±SD and % CV) of plasma and whole blood pharmacokinetic parameters for total radioactivity following a single 175 mg oral administration of XL184 (L-malate salt) containing [¹⁴C]XL184 (100 μCi) to healthy male subjects as shown below in Table 7.

TABLE 7 Plasma and whole blood pharmacokinetic parameters for total radioactivity following a single 175 mg oral administration of XL184 % Ratio of Plasma to Parameters Plasma Whole Blood Whole Blood C_(max), ngEq/mL 2000 ± 429 (21) 1200 ± 243 (20)  167 ± 12.4 (7) t_(max), h^(a) 2.00 (1.00, 4.00) 2.00 (1.98, 2.00) NA AUC_(0-t), h · ngEq/mL 259000 ± 42700 (16) 54100 ± 10300 (19)  487 ± 73.3 (15) AUC₀₋₂₄, h · ngEq/mL 31400 ± 6380 (20) 19600 ± 3780 (19)  160 ± 6.65 (4) AUC₀₋₇₂, h · ngEq/mL  89700 ± 19000 (21) 54100 ± 10300 (19) 165 ± 11.1 (7) AUC_(0-inf), h · ngEq/mL 306000 ± 59500 (19) NR NA k_(el), l/h  0.00308 ± 0.00182 (59) NR NA t_(1/2), h  269 ± 93.2 (35) NR NA ^(a)median (range); NR: Not Reportable (since AUC_(0-t)/AUC_(0-inf) ratio < 0.80); NA: Not Applicable C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; ngEq, an equivalent amount of XL184 freebase required to produce a measured or calculated amount of total radioactivity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life.

Following a single oral dose, the peak radioactivity in plasma and whole blood was achieved at approximately 2 hours (median) with a mean C_(max) of 2000 and 1200 ngEq/mL, respectively. The mean elimination half-life value for the total radioactivity in plasma was 269 hours. The mean values of systemic exposures (AUC₀₋₂₄ and AUC₀₋₇₂) in plasma were around 1.6 times higher than those in whole blood.

Radioactivity present in erythrocytes and whole blood

The percent total mean radioactivity concentration present in erythrocytes relative to whole blood ranged from 0.174±4.51 to 12.3±3.71 within 72 hours after single dosing, indicating that radioactivity was present primarily in plasma and not markedly associated with red blood cells.

Pharmacokinetic parameters of XL184 and its metabolites in plasma

XL184 and metabolites XL184 half-dimer, XL184-N-oxide, XL184-sulfate, and para fluoroaniline (p-FA) were measured in plasma samples from healthy male subjects following a single 175 mg oral administration of XL184 containing [¹⁴C]XL184 (100 μCi) by a validated LC/MS/MS method. The p-FA concentrations were below the lower limit of quantification at all time points for all subjects. A summary of plasma pharmacokinetic parameters for XL184 and metabolites XL184 half-dimer, XL184-N-oxide, and XL184 sulfate is presented in the following table.

Summary (mean±SD, and % CV) of plasma pharmacokinetic parameters for XL184 and selected metabolites following a single 175 mg oral administration of XL184 (L malate salt) containing [¹⁴C] XL184 (100 μCi) to healthy male subjects determined by a validated LC/MS/MS method as shown below in Table 8.

TABLE 8 Plasma pharmacokinetic parameters for XL184 and selected metabolites following a single 175 mg oral administration of XL184 Parameters XL184 XL184-Half-Dimer XL184-N-Oxide XL184-Sulfate C_(max), ng/mL 1250 ± 238 (19) 52.9 ± 17.3 (33)  118 ± 33.7 (28)  236 ± 66.7 (28) T_(max), h^(a) 1.49 (1.00, 3.00) 18.99 (5.00, 24.10) 13.50 (2.00, 24.30) 24.00 (3.00, 48.00) AUC₀₋₂₄, h · ng/mL 14300 ± 2600 (18) 1080 ± 341 (32)  2030 ± 682 (34)  3970 ± 1350 (34) AUC₀₋₇₂, h · ng/mL 35000 ± 6770 (19) 3120 ± 976 (31)  5610 ± 1940 (35) 12600 ± 4180 (33)  AUC_(0-t), h · ng/mL 67200 ± 6880 (10) 6540 ± 1680 (26) 10100 ± 3210 (32)  28900 ± 10700 (37) Ratio ^(b), % NA 9.93 ± 3.20 (32) 15.0 ± 3.80 (25) 42.9 ± 14.4 (33) Ratio ^(c), %  60.2 ± 7.05 (12) 5.97 ± 1.91 (32) 8.82 ± 1.48 (17) 25.0 ± 6.60 (26) AUC_(0-inf), h · ng/mL 68000 ± 6910 (10) 6770 ± 1700 (25) 10300 ± 3170 (31)  29500 ± 10600 (36) k_(el), l/h  0.00712 ± 0.00176 (25) 0.00807 ± 0.00218 (27) 0.00846 ± 0.00256 (30) 0.00859 ± 0.0022 (26)  t_(1/2), h  102 ± 23.3 (23) 91.8 ± 25.4 (28) 89.2 ± 29.2 (33) 86.0 ± 24.3 (28) ^(a)median (range); ^(b) ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(c) ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 3 measured metabolites); NA: Not Applicable; C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life.

The main circulating compound in plasma was XL184, which was rapidly absorbed after oral administration and eliminated relatively slowly. Following a single oral dose, the mean peak concentrations of XL184, XL184-half-dimer, XL184-N-oxide, and XL184-sulfate in plasma were achieved at approximately 1.49, 18.99, 13.50, and 24.00 hours (median) with a mean C_(max) of 1250, 52.9, 118 and 236 ng/mL, respectively. The mean estimated elimination half-lives of XL184, XL184-half-dimer, XL184-N-oxide, and XL184-sulfate were 102, 91.8, 89.2, and 86.0 hours, respectively.

For metabolites XL184-half-dimer, XL184-N-oxide, and XL184-sulfate, the mean metabolite exposure ratios relative to parent XL184 (AUC0-t (metabolite)/AUC0-t (parent)) were 9.93%, 15.0%, and 42.9%, respectively. Mean exposure ratios for parent and metabolites XL184 half dimer, XL184-N-oxide and XL184-sulfate relative to total exposure (AUC0-t (each analyte)/AUC0-t (parent+3 measured metabolites)) were 60.2% 5.97%, 8.82%, and 25.0%, respectively.

Safety Results:

There were no deaths, other SAEs, discontinuations due to AEs, or other significant AEs reported during the study. No subject vomited within 4 hours of dosing. Six subjects (75%) reported a total of 36 TEAEs, the majority of which were mild in severity (CTCAE grade 1). The exception was one event of treatment related dizziness, which was moderate (CTCAE grade 2) in severity. Most TEAEs (31/36, 86%) resolved within 1 to 3 days.

Apart from the preferred terms ‘headache’ and ‘flatulence,’ which were both reported in three (37.5%) subjects, all other preferred terms were reported in only one subject each. Five subjects (62.5%) reported TEAEs that were assessed as related to the study treatment.

There were no clinically significant changes from baseline in any laboratory values. No remarkable on study results were noted for vital signs or ECG evaluations.

Conclusion: Every attempt was made to keep the subjects in the clinic to obtain 90% recovery of the administered radioactivity.

Following oral administration of a single 175 mg dose of XL184 (L-malate salt) containing 100 μCi [¹⁴C]-XL184, a mean recovery of total radioactivity of 81.09% was achieved within 48 days. Less than 1% total mean radioactivity was recovered in feces and urine after Day 28 post-dose. The radioactivity was mainly eliminated in feces: (53.79%) and the remainder in urine (27.29%). The peak radioactivity in plasma and whole blood was achieved at approximately 2 hours (median) with a mean C_(max) of 2000 and 1200 ngEq/mL, respectively. The elimination half life of the total radioactivity in plasma was determined with a mean value of 269 hours. The mean values of systemic exposures (AUC₀₋₂₄ and AUC₀₋₇₂) in plasma were around 1.6 times higher than those in whole blood. The mean percent total radioactivity concentrations associated with erythrocytes relative to whole blood indicated that radioactivity was present primarily in plasma and not markedly associated with red blood cells.

The main circulating compound in plasma was XL184, which was rapidly absorbed after oral administration and eliminated relatively slowly. Following a single oral dose, the mean peak concentrations of XL184 and metabolites XL184-half-dimer, XL184-N-oxide, and XL184 sulfate in plasma were achieved at approximately 1.49, 18.99, 13.50, and 24.00 hours (median) with a mean C_(max) of 1250, 52.9, 118, and 236 ng/mL, respectively; the mean estimated elimination half-lives were 102, 91.8, 89.2, and 86.0 hours, respectively.

For metabolites XL184-half-dimer, XL184-N-oxide, and XL184-sulfate, the mean metabolite exposure ratios relative to parent XL184 (AUC0-t (metabolite)/AUC0-t (parent)) were 9.93%, 15.0%, and 42.9%, respectively. Mean exposure ratios for parent and metabolites XL184 half dimer, XL184-N-oxide, and XL184-sulfate relative to total exposure (AUC0-t (each analyte)/AUC0-t (parent+3 measured metabolites)) were 60.2%, 5.97%, 8.82%, and 25.0%, respectively.

The treatment was well tolerated. There were no deaths, other SAEs, discontinuations due to AEs, or other significant AEs. Six subjects (75%) reported a total of 36 TEAEs, the majority of which were mild in severity (CTCAE grade 1); none were severe. Apart from the preferred terms ‘headache’ and ‘flatulence,’ which were both reported in three (37.5%) subjects, all other preferred terms were reported in only one subject each. Most TEAEs were transient and resolved within 1 to 3 days. There were no notable clinical laboratory findings, or other safety concerns.

Embodiments

The invention is further defined by the following non-limiting embodiments.

Embodiment 1. A liquid pharmaceutical formulation comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein:

R¹ is halo;

R² is halo; and

Q is CH or N.

Embodiment 2. The liquid pharmaceutical composition according to embodiment 1, wherein the compound of formula I is compound 1, or a pharmaceutically acceptable salt thereof.

Embodiment 3. The liquid pharmaceutical composition according to embodiment 2, wherein compound 1 is the L-malate salt (or S-malate salt).

Embodiment 4. The liquid pharmaceutical composition according to embodiment 2, wherein compound 1 is the D-malate salt (or R-malate salt).

Embodiment 5. The liquid formulation composition according to any one of embodiments 1-4, wherein the amount of the compound of Formula I or compound 1, or a pharmaceutically acceptable salt thereof present in the liquid formulation, ranges from about 1 mg to about 200 mg.

Embodiment 6. The liquid pharmaceutical composition according to embodiment 5, wherein the amount of the compound of Formula I or compound 1, or a pharmaceutically acceptable salt thereof present in the liquid formulation is about 60 mg, or about 40 mg, or about 20 mg of the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof.

Embodiment 7. The liquid pharmaceutical composition according to embodiment 1, wherein the liquid formulation provides a smaller inter-subject variability in exposure (% CV of about 10% for AUC₀₋₄ and AUC_(0-inf); reference: Lacy et al, 2015 DMD 43:1190-1207) relative to the tablet formulation ((% CV of about 44% for AUC_(0-t) and about 46% for AUC_(0-inf); reference: Nguyen et al, 2016 Anticancer Drugs 27:669-78) upon administration of a single dose of the liquid pharmaceutical composition.

Embodiment 8. A method of treating locally advanced or metastatic solid tumors, comprising administering a patient in need of such treatment, a liquid pharmaceutical composition comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof or a liquid pharmaceutical composition comprising the compound of formula I or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein:

R¹ is halo;

R² is halo; and

Q is CH or N,

and wherein administration of a single dose of the liquid pharmaceutical composition to the patient, provides a smaller inter-subject variability in exposure (% CV of about 10% for AUC_(0-t) and AUC_(0-inf)s; reference: Lacy et al, 2015 DMD 43:1190-1207) relative to the tablet formulation ((% CV of about 44% for AUC_(0-t) and about 46% for AUC_(0-inf); reference: Nguyen et al, 2016 Anticancer Drugs 27:669-78).

Embodiment 9. The method according to embodiment 8, wherein the compound of formula I is compound 1, or a pharmaceutically acceptable salt thereof.

Embodiment 10. The method according to embodiment 9, wherein compound 1 is administered as the L-malate salt (or S-malate salt).

Embodiment 11. The method according to embodiment 9, wherein compound 1 is administered as the D-malate salt (or R-malate salt).

Embodiment 12. The method according to any one of embodiments 8-11, wherein the locally advanced or metastatic solid tumors is advanced UC or RCC.

Embodiment 13. The method according to embodiment 9, wherein compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient in a liquid pharmaceutical composition once daily with fasting in an amount of 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10 mg, or 5 mg.

Embodiment 14. The method according to embodiment 13, wherein compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient in a liquid pharmaceutical composition once daily with fasting in an amount of 60 mg, 40 mg, or 20 mg.

Embodiment 15. The method according to any one of embodiments 9-14, wherein a complete serological response is observed in patients being treated with the liquid pharmaceutical composition comprising compound 1, or a pharmaceutically acceptable salt thereof.

Embodiment 16. The method according to any one of embodiments 9-14, wherein a serological partial response is observed in patients being treated with compound 1, or a pharmaceutically acceptable salt thereof.

Embodiment 17. The method according to any one of embodiments 9-14, wherein stable disease is observed in patients being treated with compound 1, or a pharmaceutically acceptable salt thereof.

Preparation of Compound 1

Preparation of 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (Compound A-1)

The starting 1,1-cyclopropanedicarboxylic acid was treated with thionyl chloride (1.05 equivalents) in approximately 8 volumes of isopropyl acetate at 25° C. for 5 hours. The resulting mixture was then treated with a solution of 4-fluoroaniline (1.1 equivalents) and triethylamine (1.1 equivalents) in isopropyl acetate (2 volumes) over 1 hour. The product slurry was quenched with 5N NaOH solution (5 volumes), and the aqueous phase was discarded. The organic phase was extracted with 0.5N NaOH solution (10 volumes), and the basic extract was washed with heptane (5 volumes) and subsequently acidified with 30% HCl solution to give a slurry. Compound A-1 was isolated by filtration.

Compound A-1 was prepared on a 1.00 kg scale using 1,1-cyclopropanedicarboxylic acid as the limiting reagent to furnish 1.32 kg of Compound A-1 (77% isolated yield; 84% mass balance) with 99.92% purity (HPLC) and 100.3% assay.

Preparation of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) and the (L)-Malate Salt Thereof

A synthetic route that can be used for the preparation of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the (L)-malate salt thereof is depicted in Scheme 1.

Another synthetic route that can be used for the preparation of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the (L)-malate salt thereof is depicted in Scheme 2.

Preparation of 4-Chloro-6,7-dimethoxy-quinolone

A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60° C., and phosphorus oxychloride (POCl₃, 130.6 kg) was added. After the addition of POCl₃, the temperature of the reaction mixture was raised to approximately 77° C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7° C. and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26% NH₄OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25° C., and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to −20 to −25° C. and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25° C. under nitrogen to afford the title compound (35.6 kg).

Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine

4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide (21.4 kg), and DMA (167.2 kg) at 20-25° C. This mixture was then heated to 100-105° C. for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2% starting material remaining), the reactor contents were cooled at 15 to 20° C., and water (pre-cooled, 2 to 7° C., 587 L) was charged at a rate to maintain 15 to 30° C. temperature. The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg), and finally washed with water (214 L). The filter cake was then dried at approximately 25° C. on filter to yield crude 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75° C.) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour, then cooled to 0 to 5° C., and aged for approximately 1 hour, after which time the solid was filtered, washed with THF (147.6 kg), and dried on a filter under vacuum at approximately 25° C. to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).

Alternative Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine

4-chloro-6,7-dimethoxyquinoline (34.8 kg), 4-Aminophenol (30.8 kg), and sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 weight percent in THF) were charged to a reactor, followed by N,N-dimethylacetamide (DMA, 293.3 kg). This mixture was then heated to 105 to 115° C. for approximately 9 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2% starting material remaining), the reactor contents were cooled at 15 to 25° C., and water (315 kg) was added over a two hour period while maintaining the temperature between 20 and 30° C. The reaction mixture was then agitated for an additional hour at 20 to 25° C. The crude product was collected by filtration and washed with a mixture of 88 kg water and 82.1 kg DMA, followed by 175 kg water. The product was dried on a filter drier for 53 hours. The LOD showed less than 1% w/w.

In an alternative procedure, 1.6 equivalents of sodium tert-pentoxide were used, and the reaction temperature was increased from 110 to 120° C. In addition, the cool down temperature was increased to 35 to 40° C., and the starting temperature of the water addition was adjusted to 35 to 40° C., with an allowed exotherm to 45° C.

Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride

Oxalyl chloride (12.6 kg) was added to a solution of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and N, N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch temperature did not exceed 25° C. This solution was used in the next step without further processing.

Alternative Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride

A reactor was charged with 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (35 kg), DMF (344 g), and THF (175 kg). The reaction mixture was adjusted to 12 to 17° C., and then to the reaction mixture was charged 19.9 kg of oxalyl chloride over a period of 1 hour. The reaction mixture was left stirring at 12 to 17° C. for 3 to 8 hours. This solution was used in the next step without further processing.

Preparation of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide

The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30° C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25° C. for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25° C. and then at approximately 45° C. under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).

Alternative Preparation of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]amide (4-fluoro-phenyl)-amide

A reactor was charged with 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1 equivalent), followed by THF (412.9 kg). To the reaction mixture was charged a solution of K₂CO₃ (48.3 kg) in water (169 kg). The acid chloride solution of described in the Alternative Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride above was transferred to the reactor containing 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine while maintaining the temperature between 20 to 30° C. over a minimum of two hours. The reaction mixture was stirred at 20 to 25° C. for a minimum of three hours. The reaction temperature was then adjusted to 30 to 25° C., and the mixture was agitated. The agitation was stopped, and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. To the remaining upper organic phase was added water (804 kg). The reaction was left stirring at 15 to 25° C. for a minimum of 16 hours.

The product precipitated. The product was filtered and washed with a mixture of water (179 kg) and THF (157.9 kg) in two portions. The crude product was dried under a vacuum for at least two hours. The dried product was then taken up in THF (285.1 kg). The resulting suspension was transferred to reaction vessel and agitated until the suspension became a clear (dissolved) solution, which required heating to 30 to 35° C. for approximately 30 minutes. Water (456 kg) was then added to the solution, as well as SDAG-1 ethanol (20 kg, ethanol denatured with methanol over two hours). The mixture was agitated at 15 to 25° C. for at least 16 hours. The product was filtered and washed with a mixture of water (143 kg and 126.7 kg THF (143 kg) in two portions. The product was dried at a maximum temperature set point of 40° C.

In an alternative procedure, the reaction temperature during acid chloride formation was adjusted to 10 to 15° C. The recrystallization temperature was changed from 15 to 25° C. to 45 to 50° C. for 1 hour and then cooled to 15 to 25° C. over 2 hours.

Preparation of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide, cabozantinib (L) malate salt

Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor, and the mixture was heated to reflux (approximately 74° C.) for approximately 2 hours. The reactor temperature was reduced to 50 to 55° C., and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg), and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1133.2 kg) (approximate residual volume 711 L; KF <0.5% w/w) at approximately 74° C. The temperature of the reactor contents was reduced to 20 to 25° C. and held for approximately 4 hours, resulting in solid precipitate which was filtered, washed with MEK (448 kg), and dried under vacuum at 50° C. to afford the title compound (45.5 kg).

Alternative Preparation of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]amide (4-fluoro-phenyl)-amide, (L) malate salt

Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (47.9 kg), L-malic acid (17.2 kg), methyl ethyl ketone (658.2 kg), and water (129.1 kg) were charged to a reactor, and the mixture was heated 50 to 55° C. for approximately 1 to 3 hours and then at 55 to 60° C. for an additional 4 to 5 hours. The mixture was clarified by filtration through a 1 μm cartridge. The reactor temperature was adjusted to 20 to 25° C. and vacuum distilled with a vacuum at 150 to 200 mm Hg with a maximum jacket temperature of 55° C. to the volume range of 558 to 731 L.

The vacuum distillation was performed two more times with the charge of 380 kg and 380.2 kg methyl ethyl ketone, respectively. After the third distillation, the volume of the batch was adjusted to 18 v/w of Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide by charging methyl ethyl ketone (159.9 kg) to give a total volume of 880 L. An additional vacuum distillation was carried out by adjusting methyl ethyl ketone (245.7 kg). The reaction mixture was left with moderate agitation at 20 to 25° C. for at least 24 hours. The product was filtered and washed with methyl ethyl ketone (415.1 kg) in three portions. The product was dried under a vacuum with the jacket temperature set point at 45° C.

In an alternative procedure, the order of addition was changes so that a solution of L-malic acid (17.7 kg) dissolved in water (129.9 kg) was added to Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (48.7 kg) in methyl ethyl ketone (673.3 kg).

EXAMPLE 1 Phase I Study of Mass Balance Study of Cabozantinib (L-Malate Salt) Following a Single 175 mg Oral Administration of [¹⁴C]-Cabozantinib (100 μCi) in Healthy Male Subjects

1. Background and Rationale

1.1 Background

Multi-targeted tyrosine kinase inhibitors (TKIs) and checkpoint inhibiting immunotherapies represent two systemic modalities that have been instrumental in the recent advancements of anticancer treatment over the past several years. Both classes of therapies have demonstrated broad clinical effects leading to new approved treatment options across multiple tumor types including renal cell carcinoma (RCC), urothelial carcinoma (UC), melanoma, non-small-cell lung cancer (NSCLC), and others. The success of these therapy types as single agents with distinct mechanisms of action has naturally led to interest in evaluating combinations of TKIs with checkpoint inhibitors in search of further, possibly synergistic, anticancer clinical effects.

XL184 is a new chemical entity that inhibits multiple receptor tyrosine kinases implicated in tumor growth and neoangiogenesis. The primary targets of XL184 are hepatocyte growth factor receptor protein (MET), vascular endothelial growth factor receptor 2 (VEGFR2), and rearranged during transfection (RET) proto-oncogene.

XL184 is orally bioavailable as demonstrated by pharmacokinetic (PK) studies in rodent and non-rodent models. In in vivo target modulation studies, administration of XL184 to mice resulted in dose-dependent inhibition of MET, VEGFR2, and RET (Yakes, et al. 2011). Immunohistochemistry studies demonstrate rapid effects on the endothelium, vascular breakdown, and tumor cell death within 24 hours after administration of XL184. This effect translates into significant tumor growth inhibition after XL184 treatment in multiple tumor models. Additionally, in the models tested (human medullary thyroid cancer, human breast cancer, and rat glioma), marked tumor regression was observed.

Clinical activity with the use of XL184 in a variety of tumor settings has been reported and the drug is currently being developed for use in oncology.

1. Introduction

The pharmacokinetic (PK) and statistical analyses of plasma, whole blood, urine and feces concentration, and total radioactivity data were performed and reported in the Clinical Pharmacokinetic Report for the Study XL184-012.

2. Study Objectives

The objectives of the study were:

(1) To determine the time-course for excretion of ¹⁴C radioactivity in urine in healthy male subjects following a single oral dose of the study drug.

(2) To determine the time-course for excretion of ¹⁴C radioactivity in feces in healthy male subjects following a single oral dose of the study drug.

(3) To determine the recovery of ¹⁴C radioactivity as a percentage of administered dose.

(4) To determine the plasma pharmacokinetics (PK) of ¹⁴C radioactivity in healthy male subjects following a single oral dose of the study drug.

(5) To determine the whole blood pharmacokinetics (PK) of ¹⁴C radioactivity in healthy male subjects following a single oral dose of the study drug.

(6) To determine the percentage of ¹⁴C radioactivity associated with erythrocytes in whole blood over time.

(7) To determine the plasma pharmacokinetics (PK) of XL184 and its metabolites by LC/MS/MS in healthy male subjects following a single oral dose of the study drug.

(8) To determine the urine pharmacokinetics (PK) of XL184 and its metabolites in healthy male subjects using a radio-quantitative method following a single oral dose of the study drug.

(9) To determine the feces pharmacokinetics (PK) of XL184 and its metabolites in healthy male subjects using a radio-quantitative method following a single oral dose of the study drug.

(10) To determine the plasma pharmacokinetics (PK) of XL184 and its metabolites in healthy male subjects using a radio-quantitative method following a single oral dose of the study drug.

3. Investigation Plan

3.1 Summary of Study Design

The clinical phase of the study was conducted from 15 Mar. 2011, through 7 Jun. 2011. This study was designed as an open-label, single-dose, mass balance study conducted in 8 healthy male subjects at one study center in the US. Additional subjects would be enrolled only to replace any dosed subjects who drop out of the study prior to recovery of at least 85% of the radioactive dose in the subject's vomitus, urine, and feces. The primary endpoints of the study were time course for excretion of ¹⁴C radioactivity in urine and feces; the recovered percentage of the total dose of ¹⁴C radioactivity; and the percentage of ¹⁴C radioactivity present as XL184 in plasma and whole blood at selected time points.

Subjects received a single calculated oral dose intended to contain a total of 175 mg of XL184 (L-Malate Salt) containing 100 μCi of ¹⁴C.

3.1.1 Identity of Investigational Product(s)

-   -   Name: XL184     -   Active Compound: XL184     -   Activity: Cancers     -   Route of Administration: Oral     -   Dose/Solution: 175 mg XL184 (L-Malate Salt) Containing ¹⁴C XL184         (100 μCi)

3.2 Pharmacokinetic Evaluations and Metabolic Profiling Samples

3.2.1 Blood Sample Collections

Plasma

Blood samples for plasma for analysis of total radioactivity (10 mL each) and for PK analysis of XL184 and/or metabolite concentrations (3 mL each) were collected predose (within the 15 minutes prior to dose) and at 0.5, 1, 2, 3, 4, 5, 8, 14, 24, 48, 72, 120, 144, 168, 240, 336, 408, 504, and 648 hours post-dose. Blood samples for plasma for possible metabolic profiling (10 mL each) were collected pre-dose (within the 15 minutes prior to dose) and at 0.5, 1, 2, 3, 4, 5, 8, 14, 24, 72, 168, 336, 504, and 648 hours post-dose. Prior to study initiation, the Celerion Scintillation Laboratory and the laboratory performing the XL184/metabolite analysis and metabolic profiling (QPS, LLC) supplied to the Celerion clinic complete written instructions for collection, aliquot volume required for analysis, handling, processing, and shipping (if applicable) of samples. All samples collected for radioactivity analysis were analyzed for total radioactivity.

If radioactivity was present in the plasma samples, individual samples at selected time points were analyzed for XL184 and/or metabolites content and metabolic profiling as determined by the sponsor.

Whole Blood

Blood samples (4 mL) for whole blood analysis of total radioactivity were collected within 15 minutes pre-dose and at 1, 2, 4, 8, 14, 24, and 72 hours post-dose. Prior to study initiation, the Celerion Scintillation Laboratory supplied to the Celerion clinic complete written instructions for collection, handling, and processing of samples. Samples collected were used to determine the percentage of radioactivity associated with erythrocytes in whole blood over time (calculated only for time points that whole blood was collected).

3.2.2 Urine

Urine samples were collected for the analysis of total radioactivity and for possible analysis for XL184 and/or metabolites and possible metabolic profiling. Subjects were asked to empty their bladders within approximately 60 minutes prior to dosing for the pre-dose sample. Samples were collected during the 0 to 8 hours and 8 to 24 hours post-dose intervals, and then continuing in 24-hour intervals through Day 49. For subjects who met early release criteria, sampling could cease upon discharge from the clinic. Six subjects were contained in the clinic through 1152 hours (Day 49). One subject was released from the clinic following the 816 hour interval (Day 35) collection and was allowed to home-collect excreta through 1152 hours. One subject was released from the clinic following the 864 hour interval (Day 37) collection and no longer provided excreta samples.

Urine was refrigerated during the collection intervals. Subjects were instructed to urinate at the end of each collection period, if possible. The total volume collected for each interval was recorded. At the end of each collection interval, the urine was mixed to suspend any sediment and the appropriate aliquots were removed. After preparing the necessary aliquots, the remaining samples were destroyed.

Prior to study initiation, the Celerion Scintillation Laboratory and the laboratory performing the XL184/metabolite analysis and metabolic profiling (QPS, LLC) supplied to the Celerion clinic complete written instructions for collection, aliquot volume required for analysis, handling, processing, and shipping (if applicable) of samples. All samples collected for radioactivity were analyzed. If radioactivity was present in the urine samples, individual samples at selected time points might be analyzed for XL184 and/or metabolites content and metabolic profiling as determined by the sponsor.

3.2.3 Feces

Subjects were asked to bring a pre-dose stool sample with them at check-in (produced within 24 hours of check-in). Stools produced between subject check-in and dosing were collected for the pre-dose sample as well, and the sample produced nearest to dosing was used as the pre-dose sample. Post-dose stools were collected in 24-hour intervals through the morning of Day 49. For subjects who met early release criteria, sampling could cease upon discharge from the clinic. Six subjects were contained in the clinic through 1152 hours (Day 49). One subject was released from the clinic following the 816 hour interval (Day 35) collection and was allowed to home-collect excreta through 1152 hours. One subject was released from the clinic following the 864 hour interval (Day 37) collection and no longer provided excreta samples.

For each subject, multiple fecal specimens from each 24-hour interval were combined into a pre-weighed wide mouth polypropylene/polyethylene container and appropriately labeled. For each interval, the fecal sample was weighed to determine the final fecal weight. Each sample was homogenized into a slurry (approximately 20% suspension in water) from which the necessary aliquots were taken.

Prior to study initiation, the Celerion Scintillation Laboratory and the laboratory performing the XL184/metabolite analysis and metabolic profiling (QPS, LLC) supplied to the Celerion clinic complete written instructions for collection, aliquot volume required for analysis, handling, processing, and shipping (if applicable) of samples. All samples collected for radioactivity were analyzed. If radioactivity was present in the fecal samples, individual samples at selected time points might have been analyzed for XL184 and/or metabolites content and metabolic profiling as determined by the sponsor.

3.2.4 Emesis

If emesis occurred within 4 hours following dosing, it was collected (if possible) and stored for potential scintillation counting. The vomitus should have been weighed (the weight recorded in the CRF); labeled with subject number, time, and date; and placed in a freezer set at −20° C.±10° C. until it could be analyzed for radioactivity.

If emesis occurred within 4 hours of dose administration, the subject was replaced and no re-dosing of the same subject was permitted. If radioactivity recovered in vomitus in such subject was ≥85% of total administered radioactivity, the subject would have been discharged. However, if radioactivity recovered in vomitus was <85% of total administered radioactivity, the radioactivity in urine and feces produced by this subject might have been measured and monitored throughout the study upon discretion of the sponsor. A new subject might have been enrolled in the study to replace such a subject.

3.3 Drug Concentration Measurements

3.3.1 Scintillation Counting

The Celerion Scintillation Laboratory, 621 Rose Street, Lincoln, Nebr., performed sample analysis for radioactivity. All analyses were conducted in accordance with GLP.

Individual dosing containers (including the dosage form) were analyzed pre-dose and post-dose for radioactivity, with the (post-dose−pre-dose) difference being the administered dose. Whole blood, plasma, urine, feces, and emesis (if applicable) were analyzed for radioactivity content by liquid scintillation counting procedures. Whole blood and fecal samples were dried and oxidized prior to counting. Detailed reports of scintillation counting method and results for total radioactivity accompany the clinical study report.

3.3.2 Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) and Radio-Quantitative Method for XL184 and/or Metabolite Content

Plasma concentrations of XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, and XL184-Sulfate were measured using a validated LC/MS/MS method by QPS, LLC, 3 Innovation Way, Suite 240, Newark, Del. 19711, USA. Detailed reports of the bioanalytical methodologies and results accompany the clinical study report. Analyses of XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, and XL184-Sulfate were conducted in accordance with GLP. However, the newly identified metabolite, 6-Demethyl Half-Dimer Sulfate, was measured using a non-validated method by QPS, LLC and was not conducted in accordance with GLP.

The other minor metabolite in plasma, p-Fluoroaniline, was analyzed by Exelixis using a validated LC/MS/MS method. The values of p-Fluoroaniline concentrations for all the plasma samples were below the lower limit of quantitation (2.0 ng/mL). Therefore, no data will be listed for p-Fluoroaniline concentrations in this study report.

The newly identified metabolite, 6-Demethyl Half-Dimer Sulfate, was measured using non-validated method by QPS, LLC.

In addition, the plasma concentration of XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, P2, and P7 were determined using a non-GLP radio-quantitative method by QPS, LLC, 3 Innovation Way, Suite 240, Newark, Del. 19711, USA. Detailed reports of the radio-quantitative method and results can be found in the DMPK report.

3.4 Pharmacokinetic Parameters Estimation

3.4.1 Mass Balance and Blood-to-Plasma Distribution

Mass balance was calculated as the percent of total administered radioactivity recovered in urine and feces. For the purpose of calculating mass balance, the amount of administered radioactivity was defined as the total radioactivity in the dosing solution minus any radioactivity lost due to emesis (if any occurred), adsorption to the dosing cup, etc.

To determine the percentage of radioactivity associated with erythrocytes in whole blood over time (calculated only for time points where whole blood was collected), the following was calculated: the amount of radioactivity in plasma versus whole blood, adjusted for the hematocrit, at the specific time points of comparison (ETR=Xe/Xb=1−[Cp*(1-Hct)/Cb], where Cp stands for amount of radioactivity in plasma and Cb stands for the amount of radioactivity in blood and Hct stands for hematocrit value. Hematocrit values for Days-1, 2, and 4 were averaged for use in this calculation.

3.4.2 Plasma and Whole Blood

As appropriate, the PK parameters were calculated as data allowed for XL184 and/or metabolite concentrations in plasma and for radioactivity in plasma and whole blood (i.e., nanogram equivalents from radioactivity) using noncompartmental approaches. PK variables were computed using WinNonlin Professional, version 5.2. The definition for each PK variable is listed in the following table. Actual elapsed sampling times relative to [¹⁴C]-XL184 (100 μCi) oral administration were used for the estimation of PK metrics.

TABLE 9 PK Variable Definitions. C_(max) Maximum observed concentration t_(max) Time of the maximum concentration AUC_(0-t) Area under the concentration-time curve calculated using linear trapezoidal summation from time zero to time t, where t was the time of the last measurable concentration (C_(t)) AUC₀₋₂₄ Area under the concentration-time curve calculated using linear trapezoidal summation from time zero to time 24 hours AUC₀₋₇₂ Area under the concentration-time curve calculated using linear trapezoidal summation from time zero to time 72 hours AUC_(0-inf) Area under the concentration-time curve from time zero to infinity, AUC_(0-inf) = AUC_(0-t) + C_(t)/k_(el), where k_(el) was the terminal elimination rate constant k_(el) Apparent terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration vs. time curve t_(1/2) Apparent terminal elimination half-life calculated as ln(2)/k_(el) % Ratio of % Ratio of AUC_(met)/AUC_(XL184) = % (AUC_(0-t) AUC_(met)/AUC_(XL184) of metabolite)/(AUC_(0-t) of XL184) % Ratio of % Ratio of AUC_(analyte)/AUC_(XL184+Metabolites) = AUC_(analyte)/ % (AUC_(0-t) of XL184 or AUC_(XL184+Metabolites) metabolite)/(AUC_(0-t) of XL184 and metabolites)

The C_(max) and time to peak concentration (t_(max)) were directly determined from the observed blood/plasma concentrations data. AUC₀₋₂₄, AUC₀₋₇₂, and AUC_(0-t), the area under the concentration-time curve from time zero to 24 hours post dose, to 72 hours postdose, and to the time of the last measurable concentration (C_(t)), were calculated using the linear trapezoidal method.

The area under the blood/plasma concentration time curve from time zero to 24 hours postdose, to 72 hours postdose, or up to the last quantifiable concentration (AUC_(0-t)) was estimated by numerical integration using the linear trapezoidal rule (Equation 1):

$\begin{matrix} {{AUC}_{0 - t} = {\sum\limits_{i = 2}^{n}\;{0.5 \cdot \left( {C_{i} + C_{i - 1}} \right) \cdot \left( {t_{i} - t_{i - 1}} \right)}}} & {{Eq}.\mspace{14mu} 1} \end{matrix}$ where C_(i) was the blood/plasma concentration at the corresponding sampling time point of 24, 72 hours or t_(i), and n was the number of time points up to and including the last quantifiable concentration.

Estimates of half-life (t_(1/2)) were calculated using the following (Equation 2):

$\begin{matrix} {t_{1\text{/}2} = \frac{0.693}{k_{el}}} & {{Eq}.\mspace{14mu} 2} \end{matrix}$ where the value of the terminal-phase disposition rate constant (k_(el)) of the apparent phase were determined by a non-compartmental analysis using WinNonlin. A regression analysis was performed on the terminal linear phase of the semi-logarithmic plots of individual blood/plasma concentration time data. During the analysis, WinNonlin repeated regressions using the last three points with non-zero concentrations, then the last four points, and the last five, etc. Points prior to C_(max) were not used. Points with a value of zero for the dependent variable were excluded. For each regression, an adjusted R² was computed: Adjusted R ²=1−(1−R ²)*(n−1)/(n−2)  Eq. 3 where n was the number of data points in the regression, and R² was the square of the correlation coefficient. WinNonlin estimates k_(el) using the regression with the largest adjusted R², and, if the adjusted R² did not improve but was within 0.0001 of the largest adjusted R² value, the regression with the larger number of points was used. k_(el) had to be positive and calculated from at least three data points.

If the terminal phase for any individual subject failed to meet the stated criteria, the t_(1/2) were considered to be not reportable.

The area under the plasma concentration time curve up to time infinity (AUC_(0-inf)) was computed using the following (Equation 4):

$\begin{matrix} {{AUC}_{0 - \inf} = {{AUC}_{0 - t} + \frac{C_{t}}{k_{el}}}} & {{Eq}.\mspace{14mu} 4} \end{matrix}$ where C_(t) was the last measurable concentration.

3.5 Some Data Handling Procedures

If a PK profile did not contain more than five consecutive data points with a quantifiable concentration value, this PK profile was considered not evaluable by the pharmacokineticist.

Only subjects included in the pharmacokinetic analysis were included in the summary statistics.

Below the Quantification Limit (BQL):

Plasma, blood, urine, and feces concentrations below quantifiable limits (BQL) were imputed with a value of zero for the calculation of PK metrics.

The area under the concentration time curve up to time infinity (AUC_(0-inf))

AUC_(0-inf) was considered reportable if the following criteria were met:

-   -   t_(1/2) was estimable according to Section [00241].     -   AUC_(0-t)/AUC_(0-inf) ratio 0.80.

If AUC_(0-inf) for an individual subject fails any of the above criteria, the value was reported as NE or NR, where

-   -   NE: could not be estimated.     -   NR: AUC_(0-t)/AUC_(0-inf) ratio <0.80; therefore, AUC_(0-inf)         and t_(1/2) were not reportable.

Data Format (Significant Figures and Decimal Points):

Pharmacokinetic parameters were reported to 3 significant figures for individual parameters and summary statistics, with the exception of t_(max) (2 decimal places) and CV % and N, which were whole numbers (0 decimal places).

3.6 Statistical Evaluations of PK Parameters

Descriptive statistics [sample size, mean, standard deviation (SD), standard error of the mean (SEM), minimum, median, maximum, coefficient of variation, and geometric mean] were calculated for those PK parameters identified in the section describing Pharmacokinetic Parameters Estimation. No inferential statistics were calculated.

4. Pharmacokinetics Results

4.1 Data Set Analyzed

Eight subjects were enrolled and completed the study. No subject was withdrawn from the study and experienced the emesis. The statistical analysis population, therefore, consists of 8 subjects.

4.2 Pharmacokinetic Results

4.2.1 Mass Balance Results

The actual total amounts of the dose of XL184 with [¹⁴C]-radioactivity for individual subjects are listed in Table 10. The individual cumulative percent excretion of [¹⁴C]-radioactivity in the urine and feces based on total radioactivity after a single oral dose administration of XL184 (L-Malate Salt) containing [¹⁴C]-XL184 solution in eight healthy male subjects are presented in Table 16 and 17, respectively. The total cumulative percent recoveries of [¹⁴C]-radioactivity in the urine and feces based on total radioactivity after a single 175 mg oral dose administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 formulated as a solution in eight healthy male subjects is listed in Table 19.

Individual subject urine and feces cumulative excretion of total radioactivity versus time plots following a single 175 mg oral administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C] XL184 was tracked.

Mean (±SD) cumulative excretion versus time plots of total radioactivity in urine and feces following a single 175 mg oral administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C] XL184 to healthy male subjects are shown in FIG. 1.

TABLE 10 Dosing Record. XL184 Total Radioactivity Subject (mg) (μCi) 1444-1010 192.01 104.74 1444-1023 189.97 103.63 1444-1040 191.81 104.63 1444-1042 189.59 103.42 1444-1051 188.35 102.74 1444-1052 187.93 102.51 1444-1057 188.41 102.77 1444-1058 189.57 103.41

A summary of cumulative recovery of total radioactivity (as percent of dose) in the urine and feces following a single 175 mg oral administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C] XL184 to the healthy male subjects is presented in Table 11.

TABLE 11 Summary (Mean ± SD and % CV) of Cumulative Recovery of Total Radioactivity (as Percent of Dose) in Urine and Feces Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 to Healthy Male Subjects. Cumulative Recovery of Total Radioactivity (as Percent of Dose) (n = 8) Urine Feces Total 27.29 ± 4.65 (17%) 53.79 ± 4.52 (8%) 81.09 ± 1.56 (2%)

An average 27.29% (ranged from 19.78% to 34.88% based on Table 19) and 53.79% (ranged from 46.54% to 61.89% based on Table 19) of the dose was excreted in the urine and feces following the oral administration of the 175 mg XL184 containing 100 μCi [¹⁴C]-XL184 to eight male healthy volunteers, respectively. An average of 81.09% (ranged from 78.14% to 83.38% based on Table 19) of the dose was excreted in total in the urine and feces through 48 days post dose. Approximately 1% total mean radioactivity was recovered in feces and urine after Day 28 post-dose. In human radiolabel studies, total cumulative recovery of radioactivity in excreta above 80% may be considered acceptable for mass balance evaluation and sufficient recovery of radioactivity. The total recovery was considered satisfactory (81.09%), with a predominant fecal excretion of 53.79% and urine excretion of 27.29%.

4.2.2 Pharmacokinetic Results

4.2.2.1 Pharmacokinetic Parameters for Total Radioactivity in Plasma and Whole Blood

The individual and mean plasma and whole blood concentration data for [¹⁴C]-radioactivity after single dose administration of 175 mg of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 formulated as a solution in healthy male subjects are presented in Tables 22 and 23, respectively. The individual and mean hematocrit values are listed in Table 22. The individual and descriptive statistics of the percentage of ¹⁴C radioactivity associated with erythrocytes in whole blood (ETR) over time are included in Table 26. The individual actual blood sampling times of total radioactivity for plasma and whole blood are listed in Table 27.

The individual subject ¹⁴C total radioactivity in plasma and whole blood and plasma XL184 concentration (by LC/MS/MS method) versus time plots following a single 175 mg oral administration of 175 mg of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 are presented in the figures herein (linear axes) and (semi-logarithmic axes). The individual percentage of ¹⁴C radioactivity associated with erythrocytes in whole blood (ETR) over time graphs following a single oral administration of 175 mg of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 to healthy male subjects are shown in the figures and tables herein.

The individual subject and descriptive statistics for pharmacokinetic parameters of [¹⁴C]-radioactivity in plasma and whole blood are included in Table 26 and Table 27, respectively.

WinNonlin outputs of pharmacokinetic analyses of total radioactivity in plasma and whole blood data are included in the Figures and Tables herein.

FIGS. 2 and 3 (linear axes) and FIGS. 4 and 5 (semi-logarithmic axes) illustrate the mean (±SD) ¹⁴C total radioactivity in plasma and whole blood and plasma XL184 concentration (by LC/MS/MS method) versus time plots after administration of single 175 mg dose of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 formulated as an oral solution, respectively. FIG. 6 demonstrates the mean (±SD) plots of percentage of ¹⁴C radioactivity associated with erythrocytes in whole blood over time following a single 175 mg oral administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 to healthy male subjects.

A summary of plasma and whole blood pharmacokinetic parameters for total radioactivity following a single 175 mg oral administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 to healthy male subjects is presented in Table 12.

A summary (mean±SD) of the percentage of ¹⁴C radioactivity associated with erythrocytes in whole blood (ETR) over time following a single 175 mg oral administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 to healthy male subjects is presented in Table 13.

Following a single oral dose, the peak radioactivity in plasma and whole blood were achieved at approximately 2 hours (median) with a mean maximum value (C_(max)) of 2000 and 1200 ngEq/mL, respectively. The elimination half-life (t_(1/2)) of the total radioactivity in plasma was determined with a mean value of 269 hours. However, the t_(1/2), AUC_(0-inf), and AUC₀₋₇₂ of the total radioactivity in whole blood were not reportable since AUC_(0-t)/AUC_(0-inf) ratio were less than 0.80 for those eight subjects. The mean values of systemic exposures (AUC₀₋₂₄ and AUC₀₋₇₂) in plasma were around 1.6 times higher than those in whole blood (Table 12).

TABLE 12 Summary (Mean ± SD and % CV) of Plasma and Whole Blood Pharmacokinetic Parameters for Total Radioactivity following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 to Healthy Male Subjects. % Ratio of Plasma Parameters Plasma Whole Blood to Whole blood C_(max), ngEq/mL 2000 ± 429 (21) 1200 ± 243 (20)  167 ± 12.4 (7) t_(max), h^(a) 2.00 (1.00, 4.00) 2.00 (1.98, 2.00) NA AUC_(0-t), h · ngEq/mL 259000 ± 42700 (16) 54100 ± 10300 (19)  487 ± 73.3 (15) AUC₀₋₂₄, h · ngEq/mL 31400 ± 6380 (20) 19600 ± 3780 (19)  160 ± 6.65 (4) AUC₀₋₇₂, h · ngEq/mL  89700 ± 19000 (21) 54100 ± 10300 (19) 165 ± 11.1 (7) AUC_(0-inf), h · ngEq/mL 306000 ± 59500 (19) NR NA k_(el), l/h  0.00308 ± 0.00182 (59) NR NA t_(1/2), h  269 ± 93.2 (35) NR NA ^(a)median (range); NR: Not Reportable, since AUC_(0-t)/AUC_(0-inf) ratio < 0.80; NA: Not Applicable; C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution; ngEq, an equivalent amount of XL184 freebase required to produce a measured or calculated amount of total radioactivity.

The total radioactivity in whole blood and plasma was detectable in all subjects following single dosing. One of the purposes of this measurement was to characterize the partitioning of [¹⁴C]-XL184 in erythrocytes and whole blood. Erythrocyte to whole blood concentration ratios were examined after single dosing. The details of calculation used to determine the erythrocyte-to-whole blood total radioactivity concentration ratios are described in Section 3.4.1.

The mean percent of total radioactivity concentrations associated with erythrocytes based on the concentration of total radioactive concentrations in plasma and whole blood ranged from 0.174±4.51 to 12.3±3.71 within 72 hours after single dosing, indicating that radioactivity was present primarily in plasma and not markedly associated with red blood cells (Table 13).

TABLE 13 Summary (Mean ± SD and % CV) of Percentage of ¹⁴C Radioactivity Associated with Erythrocytes in Whole Blood (ETR) over Time following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 to Healthy Male Subjects. Time (hr) Percentage (%) 1 7.08 ± 5.93 (84) 2 7.85 ± 3.27 (42) 4 6.40 ± 2.05 (32) 8 12.2 ± 5.00 (41) 14 12.3 ± 3.71 (30) 24  0.174 ± 4.51 (2595) 72  3.89 ± 5.58 (143)

4.2.2.2 Plasma Pharmacokinetic Parameters for XL184 and its Metabolites by LC/MS/MS Method

The individual and mean plasma concentration data for XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate by LC/MS/MS method after single dose administration of 175 mg of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 formulated as an oral solution in healthy male subjects are presented in Tables 28 to 32A. Para-fluoroaniline (pFA) metabolite concentrations were below the LLOQ for all subjects. The individual actual plasma sampling times are listed in Table 23. The individual subject and descriptive statistics plasma pharmacokinetic parameters of XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate by LC/MS/MS method are included in Tables 33 to 36.

FIGS. 7 and 8 (linear axes) and FIGS. 9 and 10 (semi-logarithmic axes) illustrate the mean (±SD) plasma concentrations versus time plots of XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate, respectively, measured by LC/MS/MS method after administration of single 175 mg dose of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 as an oral solution.

A summary of plasma pharmacokinetic parameters of XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate measured by LC/MS/MS method following a single 175 mg oral administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 to healthy male subjects is presented in Table 14.

The parent compound, XL184, was rapidly absorbed after oral administration and eliminated relatively slowly. The main circulating metabolite in plasma was 6-Demethyl Half-Dimer Sulfate. Following a single oral dose, the mean peak concentrations of XL184, XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate in plasma were achieved at approximately 1.49, 18.99, 13.50, 24.00, and 168.00 hours (median) with a mean maximum concentration value (C_(max)) of 1250, 52.9, 118, 236 and 230 ng/mL, respectively. The mean estimated elimination half-lives of XL184, XL184-Half-Dimer, XL184-N-Oxide, and XL184-Sulfate were 102, 91.8, 89.2, and 86.0 hours, respectively (FIGS. 7, 8, 9, and 10 and Table 14). However, the elimination half-lives of 6-Demethyl Half-Dimer Sulfate for all the subjects could not be determined.

For metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate, the mean metabolite exposure ratios relative to parent XL184 (AUC_(0-t) (metabolite)/AUC_(0-t) (parent)) were 9.93%, 15.0%, 42.9%, and 150%, respectively. Mean exposure ratios for parent and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate relative to total exposure, (AUC_(0-t) (each analyte)/AUC_(0-t) (parent+4 measured metabolites)) were 32.4%, 3.09%, 4.90%, 13.8%, and 45.9%, respectively.

TABLE 14 Summary (Mean ± SD and % CV) of Plasma Pharmacokinetic Parameters for XL184 and Selected Metabolites by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects. XL184-Half- 6-Demethyl Half- Parameters XL184 Dimer XL184-N-Oxide XL184-Sulfate Dimer Sulfate* C_(max), ng/mL  1250 ± 238 (19)^(e) 52.9 ± 17.3 (33)  118 ± 33.7 (28)  236 ± 66.7 (28)  230 ± 91.2 (40) T_(max), h^(a) 1.49 (1.00, 3.00) 18.99 (5.00, 24.10) 13.50 (2.00, 24.30) 24.00 (3.00, 48.00) 168.00 (71.97, 240.00) AUC₀₋₂₄, 14300 ± 2600 (18) 1080 ± 341 (32)  2030 ± 682 (34)  3970 ± 1350 (34) 951 ± 377 (40) h · ng/mL AUC₀₋₇₂, 35000 ± 6770 (19) 3120 ± 976 (31)  5610 ± 1940 (35) 12600 ± 4180 (33)  7530 ± 3200 (42) h · ng/mL AUC_(0-t), 67200 ± 6880 (10) 6540 ± 1680 (26) 10100 ± 3210 (32)  28900 ± 10700 (37) 99500 ± 34500 (35) h · ng/mL Ratio ^(b), % NA 9.93 ± 3.20 (32) 15.0 ± 3.80 (25) 42.9 ± 14.4 (33)  150 ± 51.5 (34) Ratio ^(c), %  32.4 ± 6.07 (19)  3.09 ± 0.689 (22) 4.90 ± 2.01 (41) 13.8 ± 5.63 (41) 45.9 ± 11.2 (24) AUC_(0-inf), 68000 ± 6910 (10) 6770 ± 1700 (25) 10300 ± 3170 (31)  29500 ± 10600 (36) NA h · ng/mL k_(el), l/h  0.00712 ± 0.00176 (25) 0.00807 ± 0.00218 (27) 0.00846 ± 0.00256 (30) 0.00859 ± 0.0022 (26)  NA t_(1/2), h  102 ± 23.3 (23) 91.8 ± 25.4 (28) 89.2 ± 29.2 (33) 86.0 ± 24.3 (28) NA ^(a)median (range); ^(b) ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(c) ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 4 measured metabolites); NA: Not Applicable; C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; *The LC/MS/MS analytical method for 6-demethy half-dimer sulfate is not validated.

4.2.2.3 Plasma Pharmacokinetic Parameters for XL184 and its Metabolites using a Radio-Quantitation Method

Samples for 2 subjects were used for the investigation study. Therefore, only 6 subjects' PK profiles were determined using a radio-quantitation method. Due to the low radioactivity after 336 hours, the samples for 504 hours and 648 hours were not analyzed. The individual and mean plasma concentration data for XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, P2, and P7 using a radio-quantitative method after single dose administration of 175 mg of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 formulated as an oral solution in healthy male subjects are presented in Table 15.

The individual actual plasma sampling times are listed in Table 23. The individual subject and descriptive statistics plasma pharmacokinetic parameters of XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, P2, and P7 using a radio-quantitative method are included in Table 45. app

FIGS. 11 and 12 (linear axes) and FIGS. 13 and 14 (semi-logarithmic axes) illustrate the mean (±SD) plasma concentrations versus time plots of XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, and P7, respectively, measured by a radio-quantitative method after administration of single 175 mg dose of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 as an oral solution.

A summary of plasma pharmacokinetic parameters of XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, and P7, measured by a radio-quantitative method following a single 175 mg oral administration of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 to healthy male subjects is presented in Table 15. Since no subjects had more than five consecutive data points with a quantifiable P2 concentration value, there is no pharmacokinetic parameter information included in Table 15. The proposed major biotransformation products of XL184 are displayed in Scheme 3.

The parent compound, XL184, was rapidly absorbed after oral administration and was eliminated relatively slowly. Following a single oral dose, the median peak concentrations of XL184, XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, and P7 in plasma were achieved at approximately 1.99, 1.49, 3.00, 4.50, 71.99, 2.00, and 2.00 hours with a mean maximum concentration value (C_(max)) of 1080, 210, 299, 649, 379, 194, and 95.3 ngEq/mL, respectively. The mean estimated elimination half-lives of XL184, XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and P5 were 70.5, 57.9, 73.1, 79.2, and 73.4 hours, respectively (FIGS. 11, 12, 13, and 14 and Table 15). However, the elimination half-lives of 6-Demethyl Half-Dimer Sulfate and P7 for all the subjects were not reportable.

For metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, and P7, the mean metabolite exposure ratios relative to parent XL184 (AUC_(0-t) (metabolite)/AUC_(0-t) (parent)) were 34.4%, 34.1%, 188%, 283%, 24.5%, and 1.54%, respectively. Mean exposure ratios for parent and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, and P7 relative to total exposure (AUC_(0-t) (each analyte)/AUC_(0-t) (parent+measured metabolites) were 20.0%, 6.25%, 7.16%, 37.6%, 40.3%, 4.10%, and 0.386%, respectively.

The results of the mean metabolite exposure ratios relative to parent XL184 (AUC_(0-t) (metabolite)/AUC_(0-t) (parent)) and the mean exposure ratios for parent and metabolites relative to total exposure (AUC_(0-t) (each analyte)/AUC_(0-t) (parent+measured metabolites) between LC/MS/MS and the radio-quantitative method are different since they are two different methods. LC/MS/MS was a validated method (except for 6-Demethyl Half-Dimer Sulfate) and was run under the GLP environment in this study. On the contrary, the radio-quantitative method was not a validated method and was run under the non-GLP environment in this study.

TABLE 15 Summary (Mean ± SD and % CV) of Plasma Pharmacokinetic Parameters for XL184 and Selected Metabolites Using a Radio-Quantitative Method* Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects (N = 6). 6-Demethyl XL184-Half- XL184- Half-Dimer Parameters XL184 Dimer XL184-N-Oxide Sulfate Sulfate P5 P7 C_(max), 1080 ± 234  210 ± 73  299 ± 56  649 ± 132 379 ± 151 194 ± 51.1    95.3^(i) ngEq/mL (22) (35)  (19)  (20) (40)^(g) (26)^(h) T_(max), h^(a) 1.99 1.49 3.00 4.50 71.99 2.00          2.00^(i) (1.00, 4.00) (1.00, 24.08) (2.00, 4.00) (1.98, 24.08) (24.00, 168.00)^(g) (1.98, 5.00)^(h) AUC₀₋₂₄, 10700 ± 3170  3610 ± 1350 4300 ± 1460 11300 ± 2360  2520 ± 1370 2470 ± 1290 625^(i) h · ngEq/mL (30) (37)  (34)  (21) (54)^(g) (52)^(h) AUC₀₋₇₂, 23800 ± 9340  8680 ± 3980 10600 ± 3490  33200 ± 7940  17400 ± 7000  5950 ± 2870 625^(i) h · ngEq/mL (39) (46)  (33)  (24) (40)^(g) (48)^(h) AUC_(0-t), 38100 ± 12800 11100 ± 5890  13300 ± 8360  69900 ± 22000 89000 ± 32000 7660 ± 442  510^(i) h · ngEq/mL (34) (53)  (63)  (31) (36)^(g)  (6)^(h) Ratio^(b), % NA 34.4 ± 24.7 34.1 ± 15.4 188 ± 29.1 283 ± 200 24.5 ± 11.4      1.54^(i) (72)  (45)  (15) (71)  (47)  Ratio^(c), % 20.0 ± 6.24 6.25 ± 3.76 7.16 ± 4.20 37.6 ± 13.9 40.3 ± 15.9 4.10 ± 1.19       0.386^(i) (31) (60)  (59)  (37) (40)  (29)  AUC_(0-inf), 40300 ± 12300 16400 ± 1770  20800 ± 7640  74500 ± 22900 NA 87201^(i)          NA h · ngEq/mL (30) (11)^(d) (37)^(e) (31) k_(e1), 1/h 0.0112 ± 0.0053  0.0136 ± 0.00672 0.00976 ± 0.00212 0.00923 ± 0.00221 NA 0.00945^(i) NA (47) (49)^(d) (22)^(e) (24) t_(1/2), h 70.5 ± 23.2 57.9 ± 28.4 73.1 ± 14.0 79.2 ± 21.4 NA 73.4^(i)      NA (33) (49)^(d) (19)^(e) (27) ^(a)median (range); ^(b)ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(c)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 6 measured metabolites); NA: Not Applicable; ^(d)N = 2; ^(e)N = 3; NR: Not reportable. ^(g)N = 4; ^(h)N = 3; ^(i)N = 1; C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(e1), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life. *The radio-quantitative method was not performed according to GLP regulations.

5. Conclusions

Following oral administration of the 175 mg dose of XL184 (L-Malate Salt) containing 100 μCi [¹⁴C]-XL184 to eight male healthy volunteers, a mean recovery of total radioactivity of 81.09% was achieved within 48 days. Approximately 1% total mean radioactivity was recovered in feces and urine after Day 28 post-dose. The radioactivity was mainly eliminated in feces (53.79%) and the remainder in urine (27.29%).

Following a single oral dose, the peak radioactivity in plasma and whole blood was achieved at approximately 2 hours (median) with a mean maximum value (C_(max)) of 2000 and 1200 ngEq/mL, respectively. The elimination half-life of the total radioactivity in plasma was determined with a mean value of 269 hours. The mean values of systemic exposures (AUC₀₋₂₄ and AUC₀₋₇₂) in plasma were around 1.6 times higher than those in whole blood.

The mean percent total radioactivity concentrations associated with erythrocytes relative to whole blood ranged from 0.174±4.51 to 12.3±3.71 within 72 hours after single dosing, indicating that radioactivity was present primarily in plasma and not markedly associated with red blood cells.

XL184 was rapidly absorbed after oral administration and eliminated relatively slowly. The main circulating metabolite in plasma was 6-Demethyl Half-Dimer Sulfate. Following a single oral dose, the mean peak concentrations of XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate in plasma by LC/MS/MS method were achieved at approximately 1.49, 18.99, 13.50, 24.00, and 168.00 hours (median) with a mean maximum concentration value (C_(max)) of 1250, 52.9, 118, 236, and 230 ng/mL, respectively. The mean estimated elimination half-lives of XL184, XL184-Half-Dimer, XL184-N-Oxide, and XL184-Sulfate were 102, 91.8, 89.2, and 86.0 hours, respectively. However, the elimination half-lives of 6-Demethyl Half-Dimer Sulfate for all the subjects could not be determined. Para-fluoroaniline (pFA) metabolite concentrations were below the LLOQ for all subjects.

For metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate, the mean metabolite exposure ratios relative to parent XL184 (AUC_(0-t) (metabolite)/AUC_(0-t) (parent)) by LC/MS/MS method were 9.93%, 15.0%, 42.9%, and 150%, respectively. Mean exposure ratios for parent and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate relative to total exposure (AUC_(0-t) (each analyte)/AUC_(0-t) (parent+4 measured metabolites)) were 32.4%, 3.09%, 4.90%, 13.8%, and 45.9%, respectively.

Following a single oral dose, the median peak concentrations of XL184, XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, and P7 in plasma using a radio-quantitative method were achieved at approximately 1.99, 1.49, 2.00, 4.50, 71.99, 2.00, and 2.00 hours with a mean maximum concentration value (C_(max)) of 1080, 210, 299, 649, 379, 194, and 95.3 ngEq/mL, respectively. The mean estimated elimination half-lives of XL184, XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and P5 were 70.5, 57.9, 73.1, 79.2, and 73.4 hours, respectively

For metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, and P7, the mean metabolite exposure ratios relative to parent XL184 (AUC_(0-t) (metabolite)/AUC_(0-t) (parent)) were 34.4%, 34.1%, 188%, 283%, 24.5%, and 1.54%, respectively. Mean exposure ratios for parent and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, and P7 relative to total exposure (AUC_(0-t) (each analyte)/AUC_(0-t) (parent+measured metabolites) were 20.0%, 6.25%, 7.16%, 37.6%, 40.3%, 4.10%, and 0.386%, respectively.

The results of the mean metabolite exposure ratios relative to parent XL184 (AUC_(0-t) (metabolite)/AUC_(0-t) (parent)) and the mean exposure ratios for parent and metabolites relative to total exposure (AUC_(0-t) (each analyte)/AUC_(0-t) (parent+measured metabolites) between LC/MS/MS and the radio-quantitative method are different since they are two different methods. LC/MS/MS was a validated method (except for 6-Demethyl Half-Dimer Sulfate) and was run under the GLP environment in this study. On the contrary, the radio-quantitative method was not a validated method and was run under the non-GLP environment in this study.

TABLE 16 Individual Urine Cumulative Excretion of ¹⁴C Total Radioactivity Following Administration of a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time Time Subject Post-dose Interval 1444- 1444- 1444- 1444- 1444- 1444- 1444- 1444- Summary Statistics (Day) (hrs) 1010 1023 1040 1042 1051 1052 1057 1058 Mean SD CV % 0.33 8 0.75 1.29 1.08 2.31 1.56 1.08 1.38 1.24 1.34 0.46 34 1 24 2.32 4.30 3.22 7.81 3.81 3.89 4.78 3.38 4.19 1.64 39 2 48 4.70 8.75 6.39 14.86 7.68 8.34 9.68 7.07 8.43 3.01 36 3 72 7.26 13.09 9.22 20.34 11.00 12.23 13.67 9.75 12.07 3.96 33 4 96 9.65 16.19 11.53 24.39 13.47 15.11 16.57 12.11 14.88 4.52 30 5 120 11.74 18.60 13.44 27.04 15.59 17.46 18.91 13.86 17.08 4.77 28 6 144 13.48 20.51 14.81 28.88 16.94 19.11 20.68 15.33 18.72 4.90 26 7 168 15.03 22.11 15.82 30.27 18.00 20.49 22.01 16.62 20.04 4.95 25 8 192 16.27 23.34 16.60 31.32 19.36 21.56 23.11 18.17 21.22 4.91 23 9 216 17.35 24.24 17.22 32.02 20.33 22.44 23.99 19.02 22.08 4.86 22 10 240 18.26 25.17 17.67 32.59 21.12 23.24 24.71 19.68 22.81 4.85 21 11 264 19.07 25.95 18.05 32.99 21.78 24.03 25.27 20.23 23.42 4.82 21 12 288 19.85 26.61 18.34 33.28 22.27 24.73 25.73 20.71 23.94 4.77 20 13 312 20.51 27.11 18.55 33.54 22.61 25.24 26.07 21.05 24.34 4.75 20 14 336 21.13 27.58 18.73 33.74 23.12 25.70 26.34 21.33 24.71 4.72 19 15 360 21.69 27.98 18.88 33.91 23.45 26.14 26.60 21.59 25.03 4.70 19 16 384 22.15 28.33 18.98 34.05 23.85 26.49 26.82 21.79 25.31 4.69 19 17 408 22.54 28.64 19.08 34.16 24.21 26.80 26.99 21.96 25.55 4.67 18 18 432 22.89 28.85 19.16 34.24 24.52 27.05 27.13 22.12 25.75 4.65 18 19 456 23.22 29.10 19.23 34.32 24.81 27.28 27.25 22.24 25.93 4.65 18 20 480 23.48 29.30 19.29 34.38 25.04 27.46 27.34 22.34 26.08 4.64 18 23 504-552 24.15 29.80 19.40 34.51 25.59 27.94 27.56 22.57 26.44 4.64 18 26 576-624 24.69 30.14 19.49 34.62 25.98 28.27 27.71 22.74 26.71 4.63 17 29 648-696 25.11 30.38 19.55 34.68 26.26 28.49 27.81 22.85 26.89 4.63 17 32 720-768 25.36 30.54 19.59 34.73 26.46 28.64 27.88 22.93 27.02 4.63 17 35 792-840 25.52 30.67 19.61 34.77 26.61 28.77 27.94 22.99 27.11 4.64 17 38 864-912 25.56 30.76 19.63 34.81 26.72 28.86 27.98 23.04 27.17 4.65 17 41 936-984 25.56 30.84 19.65 34.83 26.80 28.92 28.02 23.07 27.21 4.66 17 44 1008-1056 25.56 30.90 19.78 34.85 26.86 28.98 28.04 23.11 27.26 4.64 17 47 1080-1128 25.56 30.95 19.78 34.88 26.91 29.02 28.07 23.13 27.29 4.65 17 48 1152 25.56 30.97 19.78 34.88 26.92 29.03 28.07 23.14 27.29 4.65 17

TABLE 17 Individual Feces Cumulative Excretion of ¹⁴C Total Radioactivity Following Administration of a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time Time Subject Post-dose Interval 1444- 1444- 1444- 1444- 1444- 1444- 1444- 1444- Summary Statistics (Day) (hrs) 1010 1023 1040 1042 1051 1052 1057 1058 Mean SD CV % 1 24.00 0.00 1.51 0.00 0.00 7.27 0.00 0.00 6.55 1.92 3.13 163 2 48.00 2.41 4.69 6.21 13.42 13.75 0.00 0.00 23.82 8.04 8.33 104 3 72.00 17.54 11.89 19.42 23.50 19.09 6.71 20.02 27.89 18.26 6.54 36 4 96.00 29.54 15.75 26.66 23.50 24.06 21.44 20.02 33.67 24.33 5.62 23 5 120.00 29.54 26.82 38.33 33.66 30.04 21.44 32.13 38.11 31.26 5.66 18 6 144.00 29.54 32.95 42.31 33.66 32.58 34.95 32.13 40.73 34.86 4.41 13 7 168.00 37.33 35.74 46.15 37.83 35.24 34.95 39.21 42.53 38.62 3.92 10 8 192.00 37.33 38.12 50.16 37.83 35.24 42.36 39.21 46.78 40.88 5.17 13 9 216.00 38.43 40.65 52.52 41.88 39.09 42.36 44.88 47.60 43.43 4.74 11 10 240.00 40.55 40.97 53.88 41.88 40.04 42.36 44.88 49.11 44.21 4.90 11 11 264.00 40.55 42.16 56.19 44.05 41.53 42.36 47.81 51.46 45.76 5.58 12 12 288.00 43.16 45.59 57.02 44.05 43.34 46.17 47.81 51.70 47.36 4.81 10 13 312.00 43.16 45.85 58.37 44.65 43.60 46.17 49.96 53.34 48.14 5.37 11 14 336.00 44.52 46.96 58.62 44.65 45.13 47.75 49.96 54.31 48.99 5.09 10 15 360.00 46.60 47.74 59.19 44.65 45.47 47.75 50.79 54.76 49.62 5.03 10 16 384.00 48.10 48.28 59.83 45.48 46.43 47.75 50.79 55.20 50.23 4.91 10 17 408.00 49.60 48.83 60.27 45.48 46.79 49.42 51.79 55.60 50.97 4.86 10 18 432.00 49.60 49.07 60.38 45.89 47.53 49.42 51.79 55.93 51.20 4.76 9 19 456.00 50.94 49.54 60.68 45.89 47.53 50.45 52.32 56.14 51.69 4.76 9 20 480.00 51.52 49.81 60.90 46.07 48.35 50.45 52.32 56.50 51.99 4.71 9 21 504.00 51.52 50.21 61.01 46.07 48.80 50.89 52.62 56.69 52.23 4.68 9 24 528-576 52.49 50.91 61.34 46.17 49.60 51.46 52.95 57.04 52.75 4.64 9 27 600-648 52.58 51.55 61.60 46.35 49.90 51.79 53.09 57.29 53.02 4.63 9 30 672-720 53.58 51.77 61.75 46.44 50.45 52.07 53.29 57.46 53.35 4.60 9 33 744-792 54.17 52.00 61.82 46.48 50.76 52.56 53.41 57.56 53.60 4.57 9 36 816-864 54.27 52.19 61.89 46.48 50.95 52.56 53.45 57.67 53.68 4.57 9 39 888-936 54.27 52.30 61.89 46.54 51.11 52.71 53.45 57.67 53.74 4.54 8 42  960-1008 54.27 52.41 61.89 46.54 51.22 52.81 53.45 57.67 53.78 4.52 8 45 1032-1080 54.27 52.41 61.89 46.54 51.22 52.89 53.45 57.67 53.79 4.52 8 48 1104-1152 54.27 52.41 61.89 46.54 51.22 52.89 53.45 57.67 53.79 4.52 8

TABLE 18 Individual and Mean (±SD) Total Cumulative Recoveries of XL184 Following Administration of a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [ ¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects % Dose Administered Subject Urine Feces Total 1444-1010 25.56 54.27 79.83 1444-1023 30.97 52.41 83.38 1444-1040 19.78 61.89 81.67 1444-1042 34.88 46.54 81.42 1444-1051 26.92 51.22 78.14 1444-1052 29.03 52.89 81.92 1444-1057 28.07 53.45 81.52 1444-1058 23.14 57.67 80.81 N 8 8 8 Mean 27.29 53.79 81.09 SD 4.65 4.52 1.56 SE 1.65 1.60 0.55 Min 19.78 46.54 78.14 Median 27.50 53.17 81.47 Max 34.88 61.89 83.38 CV % 17 8 2 Geometric Mean 26.94 53.63 81.07

TABLE 19 Individual and Mean Plasma ¹⁴C Total Radioactivity (ngEq/mL) Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.00 1444-1010 0.00 575.58 1170.98 1151.99 957.10 1166.03 828.28 562.37 625.13 1156.95 1444-1023 0.00 637.52 1307.24 1619.39 1679.68 1583.06 1398.91 1100.79 1072.71 1415.42 1444-1040 0.00 552.46 1494.70 2134.69 2072.76 2093.40 1824.19 1334.49 1493.87 1889.43 1444-1042 0.00 145.34 1165.20 2318.85 2358.48 2384.91 1938.98 1178.42 1366.70 2109.92 1444-1051 0.00 733.31 1703.63 1744.92 1535.99 1426.16 1209.80 926.55 949.67 1166.03 1444-1052 0.00 477.31 1296.51 2113.22 2389.04 1850.62 1538.47 1157.77 1204.02 1458.36 1444-1057 0.00 1003.35 2068.63 2189.20 1814.28 1859.70 1397.25 1177.59 1267.60 1455.06 1444-1058 0.00 677.98 1797.77 2277.56 1733.35 1788.68 1136.30 1383.22 1077.67 1461.67 N 8 8 8 8 8 8 8 8 8 8 Mean 0.00 600.36 1500.58 1943.73 1817.59 1769.07 1409.02 1102.65 1132.17 1514.11 SD 0.00 242.77 327.85 405.18 467.53 380.89 362.84 259.06 268.92 330.29 SEM 0.00 85.83 115.91 143.25 165.30 134.67 128.28 91.59 95.08 116.78 Min 0.00 145.34 1165.20 1151.99 957.10 1166.03 828.28 562.37 625.13 1156.95 Median 0.00 606.55 1400.97 2123.96 1773.82 1819.65 1398.08 1167.68 1140.85 1456.71 Max 0.00 1003.35 2068.63 2318.85 2389.04 2384.91 1938.98 1383.22 1493.87 2109.92 % CV NA 40 22 21 26 22 26 23 24 22 GM NA 537.97 1470.80 1899.92 1756.69 1731.81 1365.83 1068.66 1099.67 1484.70 GM: Geometric Mean; NA: not applicable; ngEq, an equivalent amount of XL184 freebase required to produce a measured or calculated amount of total radioactivity;

TABLE 19A Individual and Mean Plasma ¹⁴C Total Radioactivity (ngEq/mL) Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 48.00 72.00 120.00 144.00 168.00 240.00 336.00 408.00 504.00 648.00 1444-1010 663.12 694.50 539.25 470.71 454.19 305.55 245.26 206.45 156.90 99.10 1444-1023 1130.52 861.31 610.27 561.54 516.95 317.93 202.32 165.16 125.52 94.14 1444-1040 1401.38 919.12 572.28 540.07 478.14 223.79 132.95 0.00 0.00 0.00 1444-1042 1689.59 1305.59 665.59 580.54 528.51 351.79 205.62 177.55 144.52 111.48 1444-1051 1131.35 913.33 618.52 537.60 535.94 371.61 248.57 206.45 146.99 130.48 1444-1052 1080.15 861.31 606.96 579.71 494.65 402.16 307.20 227.92 184.15 151.95 1444-1057 986.01 858.83 580.54 518.60 443.45 289.86 200.67 144.52 114.79 91.66 1444-1058 1392.30 1414.60 888.56 796.90 644.12 430.24 317.11 237.83 199.84 149.47 N 8 8 8 8 8 8 8 8 8 8 Mean 1184.30 978.57 635.25 573.21 511.99 336.62 232.46 170.74 134.09 103.54 SD 310.11 247.09 108.87 97.19 63.04 66.27 60.61 75.82 61.00 48.12 SEM 109.64 87.36 38.49 34.36 22.29 23.43 21.43 26.81 21.57 17.01 Min 663.12 694.50 539.25 470.71 443.45 223.79 132.95 0.00 0.00 0.00 Median 1130.94 887.32 608.62 550.81 505.80 334.86 225.44 192.00 145.76 105.29 Max 1689.59 1414.60 888.56 796.90 644.12 430.24 317.11 237.83 199.84 151.95 % CV 26 25 17 17 12 20 26 44 45 46 GM 1146.14 953.99 628.27 566.94 508.82 330.55 225.10 NA NA NA GM: Geometric Mean; NA: not applicable; ngEq, an equivalent amount of XL184 freebase required to produce a measured or calculated amount of total radioactivity.

TABLE 20 Individual and Mean Whole Blood 14C Total Radioactivity (ngEq/mL) Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [14C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 0.00 1.00 2.00 4.00 8.00 14.00 24.00 72.00 1444-1010 0.00 717.47 763.98 742.45 395.34 432.38 701.11 452.19 1444-1023 0.00 839.78 998.26 928.49 647.70 695.94 764.84 503.00 1444-1040 0.00 916.43 1309.19 1303.16 873.37 908.68 986.20 540.04 1444-1042 0.00 776.04 1536.58 1458.20 813.08 941.41 1196.36 845.81 1444-1051 0.00 952.61 1077.50 879.40 620.14 624.45 692.49 562.44 1444-1052 0.00 817.38 1260.96 1162.77 799.30 744.17 883.70 510.76 1444-1057 0.00 1137.79 1222.20 1056.83 708.86 769.15 786.38 450.46 1444-1058 0.00 1136.07 1389.29 1048.21 821.69 720.05 854.42 764.84 N 8 8 8 8 8 8 8 8 Mean 0.00 911.70 1194.75 1072.44 709.94 729.53 858.19 578.69 SD 0.00 157.37 242.26 232.35 155.26 160.06 167.93 146.65 SEM 0.00 55.64 85.65 82.15 54.89 56.59 59.37 51.85 Min 0.00 717.47 763.98 742.45 395.34 432.38 692.49 450.46 Median 0.00 878.11 1241.58 1052.52 754.08 732.11 820.40 525.40 Max 0.00 1137.79 1536.58 1458.20 873.37 941.41 1196.36 845.81 % CV NA 17 20 22 22 22 20 25 GM NA 900.21 1171.16 1050.57 691.86 712.27 845.09 564.30 GM: Geometric Mean; NA: not applicable; ngEq, an equivalent amount of XL184 freebase required to produce a measured or calculated amount of total radioactivity

TABLE 21 Individual and Mean Hematocrit Value Hematocrit (%) Subject Day −1 Day 2 Day 4 Mean 1444-1010 40.8 41.1 39.7 40.5 1444-1023 44.6 45.7 44.2 44.8 1444-1040 41.8 44.3 42.5 42.9 1444-1042 41.7 42.0 44.6 42.8 1444-1051 42.6 41.9 42.2 42.2 1444-1052 43.9 42.5 42.0 42.8 1444-1057 48.2 46.6 46.3 47.0 1444-1058 42.6 41.9 42.2 42.2 1444-1010 43.5 41.8 42.4 42.6

TABLE 22 Individual and Descriptive Statistics of the Percentage of ¹⁴C Radioactivity Associated with Erythrocytes in Whole Blood (ETR) over Time Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 1.00 2.00 4.00 8.00 14.00 24.00 72.00 1444-1010 2.89 10.3 6.55 15.4 14.0 1.81 8.62 1444-1023 14.1 10.5 5.88 6.19 14.9 −2.15 5.48 1444-1040 6.87 6.90 8.27 12.8 6.13 −9.40 2.82 1444-1042 14.1 13.7 6.45 17.1 17.0 −0.88 11.7 1444-1051 −3.37 6.40 6.26 13.6 12.1 2.68 6.14 1444-1052 9.27 4.14 8.96 17.2 7.45 5.60 3.54 1444-1057 3.64 5.07 6.74 12.0 12.7 1.93 −1.05 1444-1058 9.17 5.90 2.05 3.37 14.1 1.80 −6.16 N 8 8 8 8 8 8 8 Mean 7.08 7.85 6.40 12.2 12.3 0.174 3.89 SD 5.93 3.27 2.05 5.00 3.71 4.51 5.58 SEM 2.10 1.16 0.725 1.77 1.31 1.59 1.97 Min −3.4 4.1 2.1 3.4 6.1 −9.4 −6.2 Median 8.0 6.7 6.5 13 13 1.8 4.5 Max 14 14 9.0 17 17 5.6 12 % CV 84 42 32 41 30 2595 143 GM NA 7.30 5.96 10.9 11.7 NA NA ETR = Xe/Xb = 1 − [Cp × (1 − Hct)/Cb], where Cp stands for concentration of radioactivity in plasma, Cb stands for concentration of radioactivity in blood and Hct stands for hemocrit value. Hematocrit values for Days −1, 2, and 4 were averaged for use in this calculation. GM: geometric me

TABLE 23 Individual Subject Actual Blood Sampling Times for Plasma for Total Radioactivity and for Pharmacokinetic Analysis of XL184 and Its Metabolites Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) 0-24 hrs Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.00 1444-1010 0.00 0.50 1.00 2.00 3.00 4.00 5.00 7.98 13.98 24.00 1444-1023 0.00 0.50 1.00 1.98 3.00 4.00 5.00 7.98 13.98 24.00 1444-1040 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.03 1444-1042 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 13.98 24.03 1444-1051 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 13.98 24.08 1444-1052 0.00 0.50 1.00 1.98 3.00 4.00 5.00 8.00 14.00 24.10 1444-1057 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.08 1444-1058 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 23.68 48-648 hrs Subject 48.00 72.00 120.00 144.00 168.00 240.00 336.00 408.00 504.00 648.00 1444-1010 48.03 72.00 120.00 144.00 168.00 240.00 336.00 407.98 504.00 648.00 1444-1023 48.00 72.00 120.00 144.00 168.00 239.98 336.00 407.98 504.00 648.00 1444-1040 48.00 72.00 120.00 143.98 168.00 240.00 336.00 408.00 503.98 648.00 1444-1042 48.00 71.97 120.00 143.98 168.00 240.00 336.00 407.98 503.98 648.00 1444-1051 48.00 71.98 120.00 144.00 167.98 240.00 336.00 407.98 503.98 647.98 1444-1052 48.00 71.98 120.00 143.98 168.00 240.00 335.87 407.98 503.98 648.00 1444-1057 48.00 71.98 120.00 144.00 168.00 240.00 335.95 407.98 503.98 647.98 1444-1058 48.00 72.00 119.98 143.98 168.00 240.00 336.00 407.98 503.98 648.00

TABLE 24 Individual Subject Actual Blood Sampling Times for Whole Blood Analysis of Total Radioactivity Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 0.00 1.00 2.00 4.00 8.00 14.00 24.00 72.00 1444-1010 0.00 1.00 2.00 4.00 7.98 13.98 24.00 72.00 1444-1023 0.00 1.00 1.98 4.00 7.98 13.98 24.00 72.00 1444-1040 0.00 1.00 2.00 4.00 8.00 14.00 24.03 72.00 1444-1042 0.00 1.00 2.00 4.00 8.00 13.98 24.03 71.97 1444-1051 0.00 1.00 2.00 4.00 8.00 13.98 24.08 71.98 1444-1052 0.00 1.00 1.98 4.00 8.00 14.00 24.10 71.98 1444-1057 0.00 1.00 2.00 4.00 8.00 14.00 24.08 71.98 1444-1058 0.00 1.00 2.00 4.00 8.00 14.00 23.68 72.00

TABLE 25 Individual Subject Actual Blood Sampling Times for Plasma for Possible Metabolic Profiling Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.00 72.00 168.00 336.00 504.00 648.00 1444-1010 0.00 0.50 1.00 2.00 3.00 4.00 5.00 7.98 13.98 24.00 72.00 168.00 336.00 504.00 648.00 1444-1023 0.00 0.50 1.00 1.98 3.00 4.00 5.00 7.98 13.98 24.00 72.00 168.00 336.00 504.00 648.00 1444-1040 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.03 72.00 168.00 336.00 503.98 648.00 1444-1042 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 13.98 24.03 71.97 168.00 336.00 503.98 648.00 1444-1051 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 13.98 24.08 71.98 167.98 336.00 503.98 647.98 1444-1052 0.00 0.50 1.00 1.98 3.00 4.00 5.00 8.00 14.00 24.10 71.98 168.00 335.87 503.98 648.00 1444-1057 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.08 71.98 168.00 335.95 503.98 647.98 1444-1058 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 23.68 72.00 168.00 336.00 503.98 648.00

TABLE 26 Individual and Descriptive Statistics of Plasma Pharmacokinetic Parameters of Total Radioactivity Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC_(0-t) AUC₀₋₂₄ AUC₀₋₇₂ AUC_(0-inf) k_(e1) t_(1/2) Subject_ID (ngEq/mL) (h) (h · ngEq/mL) (h · ngEq/mL) (h · ngEq/mL) (h · ngEq/mL) (1/h) (h) 1444-1010 1170 1.00 216000 19400 57600 249000 0.00307 226 1444-1023 1680 3.00 244000 29600 84000 283000 0.00246 282 1444-1040 2130 2.00 210000 38700 106000 228000 0.00741 93.5 1444-1042 2380 4.00 302000 38700 120000 359000 0.00197 352 1444-1051 1740 2.00 258000 26400 78500 299000 0.00317 218 1444-1052 2390 3.00 278000 32800 86500 333000 0.00278 250 1444-1057 2190 2.00 234000 33400 84900 283000 0.00187 371 1444-1058 2280 2.00 333000 32000 99900 410000 0.00194 357 N 8 8 8 8 8 8 8 8 Mean 2000 2.38 259000 31400 89700 306000 0.00308 269 SD 429 0.92 42700 6380 19000 59500 0.00182 93.2 SEM 152 0.32 15100 2260 6720 21000 0.000644 33.0 Min 1170 1.00 210000 19400 57600 228000 0.00187 93.5 Median 2160 2.00 251000 32400 85700 291000 0.00262 266 Max 2390 4.00 333000 38700 120000 410000 0.00741 371 % CV 21 39 16 20 21 19 59 35 GM 1950 2.21 256000 30700 87900 301000 0.00278 250 GM: Geometric Mean; C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(e1), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution; ngEq, an equivalent amount of XL184 freebase required to produce a measured or calculated amount of total radioactivity.

TABLE 27 Individual and Descriptive Statistics of Whole Blood Pharmacokinetic Parameters of Total Radioactivity following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC_(0-t) AUC₀₋₂₄ AUC₀₋₇₂ Ratio^(a) Ratio^(b) Ratio^(c) Ratio^(d) Subject (ngEq/mL) (h) (h · ngEq/mL) (h · ngEq/mL) (h · ngEq/mL) (%) (%) (%) (%) 1444-1010 764 2.00 40700 13000 40700 153 531 149 142 1444-1023 998 1.98 48200 17800 48200 168 506 166 174 1444-1040 1310 2.00 60000 23400 60000 163 350 165 177 1444-1042 1540 2.00 74000 25000 74000 155 408 155 162 1444-1051 1080 2.00 46900 16800 46900 161 550 157 167 1444-1052 1260 1.98 54000 20600 54000 190 515 159 160 1444-1057 1220 2.00 49500 19800 49500 180 473 169 172 1444-1058 1390 2.00 59400 20500 59400 164 561 156 168 N 8 8 8 8 8 8 8 8 8 Mean 1200 2.00 54100 19600 54100 167 487 160 165 SD 243 0.01 10300 3780 10300 12.4 73.3 6.65 11.1 SEM 85.9 0.00 3650 1340 3660 4.39 25.9 2.35 3.92 Min 764 1.98 40700 13000 40700 153 350 149 142 Median 1240 2.00 51800 20100 51800 163 511 158 168 Max 1540 2.00 74000 25000 74000 190 561 169 177 % CV 20 0 19 19 19 7 15 4 7 GM 1170 1.99 53300 19300 53300 166 481 159 165 GM: Geometric Mean; AUC_(0-inf), ke1 and t½ were not reportable since the value of AUC_(0-t)/AUC_(0-inf) for each subject was < 0.80; ^(a), ^(b), ^(c) and ^(d)% ratio of plasma to whole blood for C_(max), AUC_(0-t), AUC₀₋₂₄ and AUC₀₋₇₂, respectively. C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; ke1, apparent terminal elimination rate constant; t½, apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution; ngEq, an equivalent amount of XL184 freebase required to produce a measured or calculated amount of total radioactivity.

TABLE 28 Individual and Mean Plasma Concentrations (ng/mL) of XL184 by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects 0-24 hrs Time (hours) Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.00 1444-1010 0.000 377.055 777.766 703.373 459.276 682.206 409.319 266.879 335.869 681.961 1444-1023 0.000 410.653 988.621 1026.742 1024.476 902.898 697.894 386.419 417.208 434.009 1444-1040 0.000 328.704 998.065 1441.786 1095.197 1063.173 970.873 687.933 487.884 860.448 1444-1042 0.000 59.305 914.945 1482.359 1310.794 1158.537 978.352 504.541 600.449 788.240 1444-1051 0.000 509.883 1240.897 953.447 793.118 732.686 547.741 382.217 366.964 435.770 1444-1052 0.000 350.200 841.426 1093.027 1319.899 1019.020 729.002 529.976 486.724 504.273 1444-1057 0.000 760.436 1403.846 1237.637 902.344 1025.043 700.088 531.908 523.762 547.776 1444-1058 0.000 488.450 1344.723 1241.830 889.579 844.899 513.445 700.302 397.419 534.139 N 8 8 8 8 8 8 8 8 8 8 Mean 0.000 410.586 1063.786 1147.525 974.335 928.558 693.339 498.772 452.035 598.327 SD 0.000 197.553 235.829 258.626 282.901 166.997 204.878 150.468 88.307 160.675 SEM 0.000 69.846 83.378 91.438 100.021 59.042 72.435 53.198 31.221 56.807 Min 0.000 59.305 777.766 703.373 459.276 682.206 409.319 266.879 335.869 434.009 Median 0.000 393.854 993.343 1165.332 963.410 960.959 698.991 517.259 451.966 540.958 Max 0.000 760.436 1403.846 1482.359 1319.899 1158.537 978.352 700.302 600.449 860.448 % CV NA 48 22 23 29 18 30 30 20 27 GM NA 344.890 1041.459 1119.787 931.654 914.828 666.511 477.461 444.581 580.567 NA: Not Applicable; GM: Geometric Mean

TABLE 28A Individual and Mean Plasma Concentrations (ng/mL) of XL184 by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects 48-648 hrs Time (hours) Subject 48.00 72.00 120.00 144.00 168.00 240.00 336.00 408.00 504.00 648.00 1444-1010 283.853 254.530 156.488 122.688 163.095 90.153 65.102 43.328 27.834 10.464 1444-1023 333.638 255.041 147.087 145.915 135.606 49.766 35.903 21.636 13.009 6.311 1444-1040 489.217 246.732 179.421 172.821 134.168 55.790 24.788 10.908 5.771 2.424 1444-1042 614.498 411.177 148.076 107.202 75.695 39.898 10.711 4.879 1.968 0.000 1444-1051 424.868 305.315 154.063 125.163 121.433 71.462 39.049 25.305 14.396 8.189 1444-1052 352.213 255.189 118.584 114.427 97.118 65.257 38.068 17.412 11.462 3.790 1444-1057 307.958 244.280 113.195 116.918 92.425 44.384 19.250 10.002 3.954 2.050 1444-1058 516.059 418.464 184.363 162.622 115.395 61.247 24.467 10.756 6.704 2.270 N 8 8 8 8 8 8 8 8 8 8 Mean 415.288 298.841 150.160 133.470 116.867 59.745 32.167 18.028 10.637 4.437 SD 116.396 74.114 25.238 24.098 28.013 16.211 16.569 12.232 8.239 3.555 SEM 41.152 26.203 8.923 8.520 9.904 5.732 5.858 4.325 2.913 1.257 Min 283.853 244.280 113.195 107.202 75.695 39.898 10.711 4.879 1.968 0.000 Median 388.541 255.115 151.070 123.926 118.414 58.519 30.346 14.160 9.083 3.107 Max 614.498 418.464 184.363 172.821 163.095 90.153 65.102 43.328 27.834 10.464 % CV 28 25 17 18 24 27 52 68 77 80 GM 401.634 291.722 148.236 131.665 113.863 57.917 28.494 14.850 8.070 NA NA: Not Applicable; GM: Geometric Mean

TABLE 29 Individual and Mean Plasma Concentrations (ng/mL) of XL184 Half-Dimer by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects 0-24 hrs Time (hours) Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.00 1444-1010 0.000 4.846 13.450 23.314 24.221 27.171 24.260 22.875 31.511 35.627 1444-1023 0.000 4.593 17.564 31.523 33.843 34.651 35.617 38.445 37.909 37.924 1444-1040 0.000 4.531 14.478 27.120 29.439 32.345 32.584 28.090 34.054 35.050 1444-1042 0.000 0.000 17.132 43.143 52.416 54.336 76.749 63.237 68.777 75.680 1444-1051 0.000 4.356 17.489 28.961 31.495 36.085 36.373 38.175 40.841 35.055 1444-1052 0.000 4.261 21.194 35.430 44.061 49.890 55.705 63.530 65.263 67.985 1444-1057 0.000 8.367 24.937 37.927 38.602 51.831 50.493 57.434 69.700 69.776 1444-1058 0.000 6.794 23.881 35.764 38.359 42.571 43.260 58.592 47.769 56.247 N 8 8 8 8 8 8 8 8 8 8 Mean 0.000 4.719 18.766 32.898 36.555 41.110 44.380 46.297 49.478 51.668 SD 0.000 2.399 4.184 6.409 8.873 10.051 16.473 16.331 16.047 17.688 SEM 0.000 0.848 1.479 2.266 3.137 3.554 5.824 5.774 5.674 6.254 Min 0.000 0.000 13.450 23.314 24.221 27.171 24.260 22.875 31.511 35.050 Median 0.000 4.562 17.527 33.477 36.101 39.328 39.817 47.940 44.305 47.086 Max 0.000 8.367 24.937 43.143 52.416 54.336 76.749 63.530 69.700 75.680 % CV NA 51 22 19 24 24 37 35 32 34 GM NA NA 18.364 32.341 35.633 40.015 41.935 43.470 47.247 49.053 NA: Not Applicable; GM: Geometric Mean

TABLE 29A Individual and Mean Plasma Concentrations (ng/mL) of XL184 Half-Dimer by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects 48-648 hrs Time (hours) Subject 48.00 72.00 120.00 144.00 168.00 240.00 336.00 408.00 504.00 648.00 1444-1010 30.648 24.554 18.190 14.057 11.729 7.495 5.228 2.998 2.084 0.000 1444-1023 36.546 24.587 16.438 15.153 12.065 5.903 2.034 1.806 1.083 0.000 1444-1040 26.242 19.464 11.095 9.729 8.353 2.927 1.209 0.000 0.000 0.000 1444-1042 56.997 42.700 17.753 13.747 9.922 4.398 1.547 0.000 0.000 0.000 1444-1051 33.055 23.197 13.375 11.927 12.076 7.066 3.887 2.509 1.813 0.000 1444-1052 56.829 46.257 21.732 19.455 16.224 8.332 5.513 2.769 1.445 0.000 1444-1057 53.673 44.053 23.839 20.401 17.365 7.257 3.352 2.045 0.000 0.000 1444-1058 48.913 35.430 25.809 23.143 16.260 8.677 3.578 1.740 0.000 0.000 N 8 8 8 8 8 8 8 8 8 8 Mean 42.863 32.530 18.529 15.952 12.999 6.507 3.294 1.733 0.803 0.000 SD 12.592 10.807 5.048 4.595 3.262 1.983 1.607 1.158 0.905 0.000 SEM 4.452 3.821 1.785 1.625 1.153 0.701 0.568 0.409 0.320 0.000 Min 26.242 19.464 11.095 9.729 8.353 2.927 1.209 0.000 0.000 0.000 Median 42.730 30.009 17.972 14.605 12.071 7.162 3.465 1.926 0.542 0.000 Max 56.997 46.257 25.809 23.143 17.365 8.677 5.513 2.998 2.084 0.000 % CV 29 33 27 29 25 30 49 67 113 NA GM 41.175 30.943 17.899 15.374 12.633 6.174 2.908 NA NA NA NA: Not Applicable; GM: Geometric Mean

TABLE 30 Individual and Mean Plasma Concentrations (ng/mL) of XL184-N-Oxide by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects 0-24 hrs Time (hours) Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.00 1444-1010 0.000 11.529 42.306 49.777 46.221 57.466 38.445 33.122 25.454 64.769 1444-1023 0.000 15.944 47.387 65.128 82.005 78.375 78.220 67.430 63.633 101.490 1444-1040 0.000 17.041 82.525 149.634 167.092 150.220 135.223 125.712 140.835 178.702 1444-1042 0.000 1.789 40.311 104.019 108.484 115.106 103.517 66.642 73.090 129.577 1444-1051 0.000 13.441 67.257 94.858 92.250 91.248 79.258 68.805 66.930 84.372 1444-1052 0.000 14.585 67.753 103.201 134.615 124.375 89.247 85.963 71.593 84.326 1444-1057 0.000 27.247 92.619 113.541 90.538 111.017 86.573 79.003 80.870 93.700 1444-1058 0.000 20.854 97.364 128.577 118.153 125.842 88.903 115.660 68.937 113.468 N 8 8 8 8 8 8 8 8 8 8 Mean 0.000 15.304 67.190 101.092 104.920 106.706 87.423 80.292 73.918 106.301 SD 0.000 7.346 22.445 32.172 36.397 29.586 26.993 29.414 31.759 35.266 SEM 0.000 2.597 7.935 11.375 12.868 10.460 9.543 10.400 11.229 12.468 Min 0.000 1.789 40.311 49.777 46.221 57.466 38.445 33.122 25.454 64.769 Median 0.000 15.265 67.505 103.610 100.367 113.062 87.738 73.904 70.265 97.595 Max 0.000 27.247 97.364 149.634 167.092 150.220 135.223 125.712 140.835 178.702 % CV NA 48 33 32 35 28 31 37 43 33 GM NA 12.572 63.787 95.996 98.865 102.671 83.180 75.094 67.779 101.778 NA: Not Applicable; GM: Geometric Mean

TABLE 30A Individual and Mean Plasma Concentrations (ng/mL) of XL184-N-Oxide by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects 48-648 hrs Time (hours) Subject 48.00 72.00 120.00 144.00 168.00 240.00 336.00 408.00 504.00 648.00 1444-1010 29.036 28.612 21.842 13.355 13.351 7.415 4.583 3.326 1.817 1.062 1444-1023 64.132 40.828 19.980 19.507 14.871 5.771 2.530 1.964 0.000 0.000 1444-1040 116.958 82.612 51.850 35.583 26.090 10.327 4.459 1.674 1.094 0.000 1444-1042 90.059 63.663 20.037 13.485 10.109 4.830 1.199 0.000 0.000 0.000 1444-1051 69.537 47.911 25.291 19.696 18.011 9.570 5.079 3.200 2.005 0.000 1444-1052 50.889 33.767 16.002 11.804 9.229 6.267 2.973 1.678 1.052 0.000 1444-1057 49.764 40.895 21.335 17.057 14.433 5.546 2.390 1.382 0.000 0.000 1444-1058 89.002 76.099 31.817 30.113 19.166 9.684 4.176 1.946 1.237 0.000 N 8 8 8 8 8 8 8 8 8 8 Mean 69.922 51.798 26.019 20.075 15.658 7.426 3.424 1.896 0.901 0.133 SD 27.918 19.992 11.423 8.517 5.428 2.154 1.349 1.049 0.816 0.375 SEM 9.870 7.068 4.039 3.011 1.919 0.761 0.477 0.371 0.289 0.133 Min 29.036 28.612 16.002 11.804 9.229 4.830 1.199 0.000 0.000 0.000 Median 66.835 44.403 21.589 18.282 14.652 6.841 3.575 1.812 1.073 0.000 Max 116.958 82.612 51.850 35.583 26.090 10.327 5.079 3.326 2.005 1.062 % CV 40 39 44 42 35 29 39 55 91 283 GM 64.709 48.563 24.374 18.696 14.883 7.156 3.136 NA NA NA NA: Not Applicable; GM: Geometric Mean

TABLE 31 Individual and Mean Plasma Concentrations (ng/mL) of XL184-Sulfate by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects 0-24 hrs Time (hours) Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.00 1444-1010 0.000 26.136 53.208 75.013 69.493 92.232 65.650 37.746 34.395 112.189 1444-1023 0.000 39.062 88.742 138.826 158.824 179.491 172.724 130.798 131.091 233.292 1444-1040 0.000 45.896 145.829 249.626 310.748 267.057 283.604 197.270 268.052 306.497 1444-1042 0.000 6.360 78.291 157.511 203.331 205.443 243.196 98.885 127.544 287.276 1444-1051 0.000 29.730 96.816 126.368 141.682 148.181 125.679 108.976 133.704 174.720 1444-1052 0.000 32.267 120.212 157.200 194.021 215.476 174.760 143.215 153.538 205.532 1444-1057 0.000 59.658 156.410 180.378 187.282 226.697 174.947 159.230 198.553 262.691 1444-1058 0.000 43.796 143.662 181.953 231.546 216.139 162.694 204.329 153.379 289.913 N 8 8 8 8 8 8 8 8 8 8 Mean 0.000 35.363 110.396 158.359 187.116 193.840 175.407 135.056 150.032 234.014 SD 0.000 15.828 36.898 50.320 69.969 53.659 66.538 54.506 66.343 66.769 SEM 0.000 5.596 13.045 17.791 24.738 18.971 23.525 19.271 23.456 23.606 Min 0.000 6.360 53.208 75.013 69.493 92.232 65.650 37.746 34.395 112.189 Median 0.000 35.665 108.514 157.356 190.652 210.460 173.742 137.007 143.542 247.992 Max 0.000 59.658 156.410 249.626 310.748 267.057 283.604 204.329 268.052 306.497 % CV NA 45 33 32 37 28 38 40 44 29 GM NA 30.490 104.387 150.767 173.768 185.812 162.613 121.946 132.738 223.841 NA: Not Applicable; GM: Geometric Mean

TABLE 31A Individual and Mean Plasma Concentrations (ng/mL) of XL184-Sulfate by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects 48-648 hrs Time (hrs) Subject 48.00 72.00 120.00 144.00 168.00 240.00 336.00 408.00 504.00 648.00 1444-1010 45.563 50.547 46.211 27.744 23.691 11.649 8.367 5.228 0.000 0.000 1444-1023 146.630 132.711 90.680 85.890 73.594 26.053 9.824 5.311 0.000 0.000 1444-1040 230.932 198.580 156.507 125.712 112.019 47.012 18.863 9.010 4.723 0.000 1444-1042 220.082 185.825 81.561 61.841 46.492 21.297 5.717 0.000 0.000 0.000 1444-1051 176.870 152.441 95.518 73.454 73.048 36.170 20.502 13.626 7.874 4.167 1444-1052 130.352 106.815 47.419 37.916 27.883 16.190 10.596 4.971 0.000 0.000 1444-1057 147.459 151.276 89.982 80.113 61.829 30.106 11.580 6.347 0.000 0.000 1444-1058 258.933 211.280 149.901 151.619 97.444 49.589 22.349 8.128 4.996 0.000 N 8 8 8 8 8 8 8 8 8 8 Mean 169.603 148.684 94.722 80.536 64.500 29.758 13.475 6.578 2.199 0.521 SD 67.915 52.708 40.823 41.620 31.252 13.782 6.195 3.916 3.175 1.473 SEM 24.011 18.635 14.433 14.715 11.049 4.873 2.190 1.384 1.123 0.521 Min 45.563 50.547 46.211 27.744 23.691 11.649 5.717 0.000 0.000 0.000 Median 162.165 151.859 90.331 76.784 67.439 28.080 11.088 5.829 0.000 0.000 Max 258.933 211.280 156.507 151.619 112.019 49.589 22.349 13.626 7.874 4.167 % CV 40 35 43 52 48 46 46 60 144 283 GM 152.912 137.642 86.953 70.735 57.000 26.794 12.223 NA NA NA NA: Not Applicable; GM: Geometric Mean

TABLE 32 Individual and Mean Plasma Concentrations (ng/mL) of 6-Demethyl Half-Dimer Sulfate by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects 0-24 hrs Time (hours) Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.00 1444-1010 0.000 0.000 0.000 0.000 3.386 5.641 8.608 15.507 34.150 51.405 1444-1023 0.000 0.000 0.000 2.592 6.599 11.121 15.479 32.187 47.455 99.900 1444-1040 0.000 0.000 0.000 0.000 2.692 3.416 6.003 10.485 18.220 27.408 1444-1042 0.000 0.000 0.000 2.376 6.406 11.906 19.210 40.794 76.906 141.432 1444-1051 0.000 0.000 0.000 2.132 5.610 8.166 12.887 24.346 50.905 71.492 1444-1052 0.000 0.000 0.000 0.000 3.763 6.466 10.265 23.612 54.607 79.917 1444-1057 0.000 0.000 0.000 0.000 3.139 5.576 8.199 17.826 44.580 71.085 1444-1058 0.000 0.000 0.000 2.672 6.542 10.442 16.258 31.365 69.308 107.045 N 8 8 8 8 8 8 8 8 8 8 Mean 0.000 0.000 0.000 1.222 4.767 7.842 12.114 24.515 49.516 81.211 SD 0.000 0.000 0.000 1.315 1.681 3.061 4.595 9.960 18.570 35.102 SEM 0.000 0.000 0.000 0.465 0.594 1.082 1.625 3.521 6.566 12.410 Min 0.000 0.000 0.000 0.000 2.692 3.416 6.003 10.485 18.220 27.408 Median 0.000 0.000 0.000 1.066 4.687 7.316 11.576 23.979 49.180 75.705 Max 0.000 0.000 0.000 2.672 6.599 11.906 19.210 40.794 76.906 141.432 % CV NA NA NA 108 35 39 38 41 38 43 GM NA NA NA NA 4.496 7.275 11.327 22.623 45.842 73.647 NA: Not Applicable; GM: Geometric Mean

TABLE 32A Individual and Mean Plasma Concentrations (ng/mL) of 6-Demethyl Half-Dimer Sulfate by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects 48-648 hrs Time (hrs) Subject 48.00 72.00 120.00 144.00 168.00 240.00 336.00 408.00 504.00 648.00 1444-1010 84.732 122.418 164.550 168.502 174.221 159.028 158.082 144.822 127.233 97.753 1444-1023 141.710 176.888 212.151 207.554 215.785 198.217 177.675 135.964 125.529 108.334 1444-1040 49.742 59.747 72.988 67.894 85.113 66.807 59.122 46.038 39.328 29.436 1444-1042 223.640 323.165 247.344 250.230 267.533 212.848 186.228 150.688 141.540 107.324 1444-1051 146.757 146.869 154.952 157.981 173.296 176.893 133.908 136.789 121.149 105.230 1444-1052 149.399 208.455 242.883 243.269 274.906 245.792 222.108 179.242 162.042 157.284 1444-1057 117.309 162.565 179.245 188.012 215.041 170.955 150.313 120.915 121.615 104.173 1444-1058 218.918 271.897 311.399 288.310 371.830 297.836 225.057 208.293 202.228 143.171 N 8 8 8 8 8 8 8 8 8 8 Mean 141.526 184.001 198.189 196.469 222.216 191.047 164.062 140.344 130.083 106.588 SD 59.831 83.504 72.171 68.143 85.190 67.604 53.336 47.147 45.942 37.702 SEM 21.153 29.523 25.516 24.092 30.119 23.902 18.857 16.669 16.243 13.330 Min 49.742 59.747 72.988 67.894 85.113 66.807 59.122 46.038 39.328 29.436 Median 144.234 169.727 195.698 197.783 215.413 187.555 167.879 140.806 126.381 106.277 Max 223.640 323.165 311.399 288.310 371.830 297.836 225.057 208.293 202.228 157.284 % CV 42 45 36 35 38 35 33 34 35 35 GM 128.687 165.608 184.175 182.634 206.142 177.656 153.681 130.546 119.974 97.637 NA: Not Applicable; GM: Geometric Mean

TABLE 33 Individual and Descriptive Statistics of XL184 Plasma Pharmacokinetic Parameters by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC₀₋₂₄ AUC₀₋₇₂ AUC_(0-t) AUC_(0-inf) k_(el) t_(1/2) Ratio^(a) Subject (ng/mL) (h) (h · ng/mL) (h · ng/mL) (h · ng/mL) (h · ng/mL) (1/h) (h) (%) 1444-1010 778 1.00 10700 28800 72100 73900 0.0058 119 39.5 1444-1023 1030 1.98 12500 28800 61300 62500 0.00512 135 30.2 1444-1040 1440 2.00 17800 42800 74300 74700 0.00625 111 43.3 1444-1042 1480 2.00 17600 46800 72900 73100 0.0101 69.0 30.7 1444-1051 1240 1.00 11600 30700 66100 67500 0.00575 121 33.0 1444-1052 1320 3.00 14500 32100 61700 62200 0.00675 103 27.6 1444-1057 1400 1.00 15300 32200 56200 56400 0.00862 80.4 29.2 1444-1058 1340 1.00 14300 38100 73300 73500 0.00856 81.0 25.6 N 8 8 8 8 8 8 8 8 8 Mean 1250 1.62 14300 35000 67200 68000 0.00712 102 32.4 SD 238 0.74 2600 6770 6880 6910 0.00176 23.3 6.07 SEM 84.1 0.26 919 2390 2430 2440 0.000623 8.25 2.15 Min 778 1.00 10700 28800 56200 56400 0.00512 69.0 25.6 Median 1330 1.49 14400 32100 69100 70300 0.0065 107 30.4 Max 1480 3.00 17800 46800 74300 74700 0.0101 135 43.3 % CV 19 46 18 19 10 10 25 23 19 GM 1230 1.49 14100 34500 66900 67700 0.00694 100 31.9 GM: Geometric Mean; ^(a)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 4 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution.

TABLE 33A Individual and Descriptive Statistics of XL184-Half-Dimer Plasma Pharmacokinetic Parameters by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC₀₋₂₄ AUC₀₋₇₂ AUC_(0-t) Ratio^(a) Ratio^(b) AUC_(0-inf) k_(el) t_(1/2) Subject (ng/mL) (h) (h · ng/mL) (h · ng/mL) (h · ng/mL) (%) (%) (h · ng/mL) (1/h) (h) 1444-1010 35.6 24.00 669 2130 5690 7.89 3.11 6080 0.00531 131 1444-1023 38.4 7.98 853 2480 5470 8.92 2.69 5610 0.00786 88.2 1444-1040 35.1 24.03 741 2030 3830 5.15 2.23 3940 0.0108 64.2 1444-1042 76.7 5.00 1530 4320 7230 9.92 3.05 7370 0.0111 62.7 1444-1051 40.8 13.98 859 2350 5470 8.28 2.73 5800 0.00557 124 1444-1052 68.0 24.10 1410 4140 8740 14.2 3.90 8950 0.00708 97.9 1444-1057 69.8 24.08 1420 4070 8270 14.7 4.30 8550 0.00757 91.6 1444-1058 58.6 8.00 1150 3430 7630 10.4 2.66 7820 0.0093 74.5 N 8 8 8 8 8 8 8 8 8 8 Mean 52.9 16.40 1080 3120 6540 9.93 3.09 6770 0.00807 91.8 SD 17.3 8.55 341 976 1680 3.20 0.689 1700 0.00218 25.4 SEM 6.10 3.02 120 345 595 1.13 0.244 600 0.000771 9.00 Min 35.1 5.00 669 2030 3830 5.15 2.23 3940 0.00531 62.7 Median 49.7 18.99 1010 2950 6460 9.42 2.89 6730 0.00772 89.9 Max 76.7 24.10 1530 4320 8740 14.7 4.30 8950 0.0111 131 % CV 33 52 32 31 26 32 22 25 27 28 GM 50.4 14.02 1030 2980 6340 9.47 3.02 6560 0.00781 88.8 GM: Geometric Mean; ^(a)ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(b)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 4 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution.

TABLE 34 Individual and Descriptive Statistics of XL184-N-Oxide Plasma Pharmacokinetic Parameters by LC/MS/MS Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC₀₋₂₄ AUC₀₋₇₂ AUC_(0-t) Ratio^(a) Ratio^(b) AUC_(0-inf) k_(el) t_(1/2) Subject (ng/mL) (h) (h · ng/mL) (h · ng/mL) (h · ng/mL) (%) (%) (h · ng/mL) (1/h) (h) 1444-1010 64.8 24.00 945 2760 6780 9.40 3.71 7000 0.00486 143 1444-1023 101 24.00 1750 4990 8640 14.1 4.25 8850 0.00928 74.7 1444-1040 179 24.03 3390 9340 16700 22.5 9.74 16800 0.0109 63.5 1444-1042 130 24.03 2100 6580 10100 13.9 4.26 10200 0.0126 54.8 1444-1051 94.9 2.00 1760 5020 10000 15.1 4.99 10300 0.00596 116 1444-1052 135 3.00 1980 4620 7700 12.5 3.44 7850 0.00684 101 1444-1057 114 2.00 2040 4850 8420 15.0 4.37 8590 0.0083 83.5 1444-1058 129 2.00 2280 6690 12700 17.3 4.44 12800 0.00895 77.4 N 8 8 8 8 8 8 8 8 8 8 Mean 118 13.13 2030 5610 10100 15.0 4.90 10300 0.00846 89.2 SD 33.7 11.64 682 1940 3210 3.80 2.01 3170 0.00256 29.2 SEM 11.9 4.11 241 686 1130 1.34 0.711 1120 0.000905 10.3 Min 64.8 2.00 945 2760 6780 9.40 3.44 7000 0.00486 54.8 Median 122 13.50 2010 5010 9320 14.5 4.31 9530 0.00863 80.5 Max 179 24.03 3390 9340 16700 22.5 9.74 16800 0.0126 143 % CV 28 89 34 35 32 25 41 31 30 33 GM 114 7.29 1930 5320 9750 14.6 4.65 9930 0.00811 85.3 GM: Geometric Mean; ^(a)ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(b)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 4 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution.

TABLE 35 Individual and Descriptive Statistics of XL184-Sulfate Plasma Pharmacokinetic Parameters by LC/MS/MS Method following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC₀₋₂₄ AUC₀₋₇₂ AUC_(0-t) Ratio^(a) Ratio^(b) AUC_(0-inf) k_(el) t_(1/2) Subject (ng/mL) (h) (h · ng/mL) (h · ng/mL) (h · ng/mL) (%) (%) (h · ng/mL) (1/h) (h) 1444-1010 112 24.00 1430 4470 11000 15.3 6.02 11900 0.00619 112 1444-1023 233 24.00 3710 11600 26900 43.9 13.2 27400 0.0095 72.9 1444-1040 311 3.00 6090 17700 43000 57.9 25.1 43500 0.00948 73.1 1444-1042 287 24.03 4020 15000 28100 38.5 11.8 28600 0.0122 56.8 1444-1051 177 48.00 3190 11400 30900 46.7 15.4 31700 0.00532 130 1444-1052 215 4.00 3920 10800 19700 31.9 8.80 20400 0.00734 94.4 1444-1057 263 24.08 4710 13200 28700 51.1 14.9 29400 0.00953 72.8 1444-1058 290 23.68 4700 16900 42700 58.3 14.9 43200 0.00913 75.9 N 8 8 8 8 8 8 8 8 8 8 Mean 236 21.85 3970 12600 28900 42.9 13.8 29500 0.00859 86.0 SD 66.7 14.04 1350 4180 10700 14.4 5.63 10600 0.00220 24.3 SEM 23.6 4.96 477 1480 3790 5.08 1.99 3750 0.000777 8.61 Min 112 3.00 1430 4470 11000 15.3 6.02 11900 0.00532 56.8 Median 248 24.00 3970 12400 28400 45.3 14.1 29000 0.00931 74.5 Max 311 48.00 6090 17700 43000 58.3 25.1 43500 0.0122 130 % CV 28 64 34 33 37 33 41 36 26 28 GM 226 16.11 3710 11800 26800 40.1 12.8 27600 0.00833 83.2 GM: Geometric Mean; ^(a)ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(b)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 4 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution.

TABLE 36 Individual and Descriptive Statistics of 6-Demethyl Half-Dimer Sulfate Plasma Pharmacokinetic Parameters by LC/MS/MS Method following a Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC₀₋₂₄ AUC₀₋₇₂ AUC_(0-t) Ratio^(a) Ratio^(b) AUC_(0-inf) k_(el) t_(1/2) Subject (ng/mL) (h) (h · ng/mL) (h · ng/mL) (h · ng/mL) (%) (%) (h · ng/mL) (1/h) (h) 1444-1010 174 168.00 627 4750 87100 121 47.7 NR NR NR 1444-1023 216 168.00 1080 7800 101000 165 49.7 NR NR NR 1444-1040 85.1 168.00 348 2590 33600 45.2 19.6 NR NR NR 1444-1042 323 71.97 1570 12500 119000 163 50.1 NR NR NR 1444-1051 177 240.00 916 7060 88000 133 43.9 NR NR NR 1444-1052 275 168.00 972 8020 126000 204 56.3 NR NR NR 1444-1057 215 168.00 816 6430 90900 162 47.2 NR NR NR 1444-1058 372 168.00 1290 11100 150000 205 52.4 NR NR NR N 8 8 8 8 8 8 8 NA NA NA Mean 230 165.00 951 7530 99500 150 45.9 NA NA NA SD 91.2 45.25 377 3200 34500 51.5 11.2 NA NA NA SEM 32.2 16.00 133 1130 12200 18.2 3.97 NA NA NA Min 85.1 71.97 348 2590 33600 45.2 19.6 NA NA NA Median 216 168.00 944 7430 96000 162 48.7 NA NA NA Max 372 240.00 1570 12500 150000 205 56.3 NA NA NA % CV 40 27 40 42 35 34 24 NA NA NA GM 212 158.00 875 6850 92400 138 44.1 NA NA NA GM: Geometric Mean; ^(a)ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(b)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 4 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution; NA: Not applicable; NR: Not reportable.

TABLE 37 Individual and Mean Plasma Concentrations (ngEq/mL) of XL184 using a Radio-Quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.00 72.00 168.00 336.00 1444-1023 0.0 325.6 706.6 894.9 752.7 675.6 511.9 349.8 251.3 254.6 101.4 51.2 10.3 1444-1040 0.0 282.6 820.7 1132.9 876.2 912.1 806.5 501.4 486.3 573.4 227.6 54.2 12.3 1444-1042 0.0 145.3 674.9 1277.2 1177.6 1493.7 556.5 480.1 525.6 630.4 303.7 30.3 0.0 1444-1051 0.0 366.7 817.9 661.5 557.9 435.3 391.9 268.4 239.9 259.6 144.4 46.0 33.3 1444-1052 0.0 150.9 439.0 880.8 1056.2 755.1 457.2 301.1 233.3 306.3 0.0 23.9 24.1 1444-1057 0.0 429.4 1077.5 1026.3 686.3 733.3 416.1 338.6 297.9 277.5 178.8 53.6 18.3 N 6 6 6 6 6 6 6 6 6 6 6 6 6 Mean 0.0 283.4 756.1 978.9 851.2 834.2 523.4 373.2 339.1 383.6 159.3 43.2 16.4 SD 0.0 115.5 210.2 215.6 233.3 358.3 151.4 95.7 131.8 171.0 104.7 13.0 11.6 SEM 0.0 47.1 85.8 88.0 95.2 146.3 61.8 39.1 53.8 69.8 42.8 5.3 4.7 Min 0.0 145.3 439.0 661.5 557.9 435.3 391.9 268.4 233.3 254.6 0.0 23.9 0.0 Median 0.0 304.1 762.3 960.6 814.5 744.2 484.6 344.2 274.6 291.9 161.6 48.6 15.3 Max 0.0 429.4 1077.5 1277.2 1177.6 1493.7 806.5 501.4 525.6 630.4 303.7 54.2 33.3 % CV NA 41 28 22 27 43 29 26 39 45 66 30 71 GM NA 261.2 730.1 958.3 824.5 778.1 507.7 363.4 319.9 355.9 NA 41.3 NA NA: Not Applicable; ND: No Data; GM: Geometric Mean

TABLE 38 Individual and Mean Plasma Concentrations (ngEq/mL) of XL184-Half-Dimer** using a Radio-Quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 0 0.5 1 2 3 4 5 8 14 24 72 168 336 1444-1023 0.0 139.5 166.1 173.5 97.2 162.4 111.4 129.1 109.6 89.2 58.2 0.0 0.0 1444-1040 0.0 81.0 85.9 77.2 76.6 67.1 66.7 52.1 60.2 75.2 0.0 0.0 0.0 1444-1042 0.0 0.0 65.7 136.3 164.3 134.3 210.1 198.0 216.3 295.1 130.0 0.0 0.0 1444-1051 0.0 132.3 213.3 198.6 186.7 138.3 158.0 98.8 154.6 124.1 69.5 31.7 0.0 1444-1052 0.0 140.9 236.4 234.6 203.0 222.9 192.0 190.2 254.7 171.2 0.0 47.7 10.7 1444-1057 0.0 204.9 235.7 160.3 166.6 183.3 137.7 137.8 172.0 175.6 78.7 12.7 0.0 N 6 6 6 6 6 6 6 6 6 6 6 6 6 Mean 0.0 116.4 167.2 163.4 149.1 151.4 146.0 134.3 161.2 155.1 56.1 15.4 1.8 SD 0.0 69.3 75.5 54.0 50.6 52.6 52.8 55.2 70.4 80.0 49.9 20.1 4.4 SEM 0.0 28.3 30.8 22.0 20.7 21.5 21.5 22.5 28.8 32.6 20.4 8.2 1.8 Min 0.0 0.0 65.7 77.2 76.6 67.1 66.7 52.1 60.2 75.2 0.0 0.0 0.0 Median 0.0 135.9 189.7 166.9 165.5 150.4 147.9 133.5 163.3 147.7 63.9 6.4 0.0 Max 0.0 204.9 236.4 234.6 203.0 222.9 210.1 198.0 254.7 295.1 130.0 47.7 10.7 % CV NA 60 45 33 34 35 36 41 44 52 89 131 245 GM NA NA 149.4 154.6 140.6 142.2 136.7 122.9 146.0 139.5 NA NA NA **Co-eluted with Demethyl XL184 glucuronide B; NA: Not Applicable; GM: Geometric Mean

TABLE 39 Individual and Mean Plasma Concentrations (ngEq/mL) of XL184-N-Oxide using a Radio-Quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 0 0.5 1 2 3 4 5 8 14 24 72 168 336 1444-1023 0.0 0.0 175.4 224.8 189.5 232.5 183.2 144.4 143.6 140.5 73.8 0.0 8.9 1444-1040 0.0 66.3 217.5 321.2 304.2 327.1 293.7 268.4 319.9 309.6 103.3 38.1 10.7 1444-1042 0.0 0.0 131.0 331.2 344.9 161.7 284.1 110.9 69.4 111.0 100.1 0.0 0.0 1444-1051 0.0 0.0 200.6 221.9 181.3 153.4 137.5 135.2 129.0 208.3 85.1 0.0 0.0 1444-1052 0.0 0.0 132.1 195.6 325.7 235.5 235.9 133.9 104.0 160.6 0.0 0.0 0.0 1444-1057 0.0 87.9 215.0 340.5 252.8 237.0 216.4 167.0 178.6 229.0 60.4 34.2 0.0 N 6 6 6 6 6 6 6 6 6 6 6 6 6 Mean 0.0 25.7 178.6 272.5 266.4 224.5 225.1 160.0 157.4 193.2 70.5 12.1 3.3 SD 0.0 40.4 39.4 65.1 69.9 63.0 59.7 56.1 87.7 71.6 38.1 18.7 5.1 SEM 0.0 16.5 16.1 26.6 28.5 25.7 24.4 22.9 35.8 29.2 15.5 7.6 2.1 Min 0.0 0.0 131.0 195.6 181.3 153.4 137.5 110.9 69.4 111.0 0.0 0.0 0.0 Median 0.0 0.0 188.0 273.0 278.5 234.0 226.2 139.8 136.3 184.5 79.5 0.0 0.0 Max 0.0 87.9 217.5 340.5 344.9 327.1 293.7 268.4 319.9 309.6 103.3 38.1 10.7 % CV NA 157 22 24 26 28 27 35 56 37 54 155 156 GM NA NA 174.7 265.9 258.3 217.3 218.0 153.3 140.3 182.5 NA NA NA NA: Not Applicable; ND: No Data; GM: Geometric Mean

TABLE 40 Individual and Mean Plasma Concentrations(ngEq/mL) of XL184-Sulfate*** using a Radio-Quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 0 0.5 1 2 3 4 5 8 14 24 72 168 336 1444-1023 0.0 167.5 270.2 350.0 568.8 575.3 543.8 405.8 422.7 381.1 280.7 115.5 41.6 1444-1040 0.0 126.4 426.4 559.5 789.6 740.4 776.3 606.7 571.2 866.9 488.1 252.7 41.0 1444-1042 0.0 0.0 247.5 504.7 589.0 452.6 718.1 207.2 264.6 630.8 418.0 101.1 15.6 1444-1051 0.0 94.8 269.3 458.4 459.9 502.0 389.9 316.1 470.7 515.7 312.6 122.3 75.3 1444-1052 0.0 132.6 362.7 541.6 459.9 535.8 532.0 402.3 366.7 501.3 248.3 0.0 18.5 1444-1057 0.0 282.5 460.4 600.8 588.5 673.9 496.0 435.0 545.0 529.2 311.0 192.8 19.4 N 6 6 6 6 6 6 6 6 6 6 6 6 6 Mean 0.0 134.0 339.4 502.5 576.0 580.0 576.0 395.5 440.2 570.8 343.1 130.7 35.2 SD 0.0 92.4 90.4 89.0 120.8 108.5 144.4 132.7 114.6 165.4 91.1 86.0 22.8 SEM 0.0 37.7 36.9 36.4 49.3 44.3 59.0 54.2 46.8 67.5 37.2 35.1 9.3 Min 0.0 0.0 247.5 350.0 459.9 452.6 389.9 207.2 264.6 381.1 248.3 0.0 15.6 Median 0.0 129.5 316.5 523.2 578.7 555.6 537.9 404.1 446.7 522.5 311.8 118.9 30.2 Max 0.0 282.5 460.4 600.8 789.6 740.4 776.3 606.7 571.2 866.9 488.1 252.7 75.3 % CV NA 69 27 18 21 19 25 34 26 29 27 66 65 GM NA NA 329.6 495.2 566.1 571.8 561.0 375.9 426.4 552.7 333.8 NA 29.9 ***Co-eluted with Half-dimer methyl ester; NA: Not Applicable; ND: No Data; GM: Geometric Mean

TABLE 41 Individual and Mean Plasma Concentrations (ngEq/mL) of Demethyl Half-Dimer Sulfate using a Radio-Quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 0 0.5 1 2 3 4 5 8 14 24 72 168 336 1444-1023 0.0 0.0 0.0 0.0 0.0 0.0 110.2 105.9 182.6 417.5 360.9 313.3 129.8 1444-1040 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 60.1 87.4 172.2 165.5 71.8 1444-1042 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 127.1 315.2 373.2 391.1 175.0 1444-1052 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 155.6 216.2 532.7 389.9 240.7 N 4 4 4 4 4 4 4 4 4 4 4 4 4 Mean 0.0 0.0 0.0 0.0 0.0 0.0 27.6 26.5 131.4 259.1 359.8 315.0 154.3 SD 0.0 0.0 0.0 0.0 0.0 0.0 55.1 53.0 52.6 140.9 147.5 106.1 71.4 SEM 0.0 0.0 0.0 0.0 0.0 0.0 27.6 26.5 26.3 70.5 73.8 53.0 35.7 Min 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 60.1 87.4 172.2 165.5 71.8 Median 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 141.4 265.7 367.1 351.6 152.4 Max 0.0 0.0 0.0 0.0 0.0 0.0 110.2 105.9 182.6 417.5 532.7 391.1 240.7 % CV NA NA NA NA NA NA 200 200 40 54 41 34 46 GM NA NA NA NA NA NA NA NA 121.4 223.3 333.4 298.2 140.8 GM: Geometric Mean; NA: Not Applicable Subjects whose PK profile did not contain more than five consecutive data points with a quantifiable concentration value. Time (hours) Subject 0 0.5 1 2 3 4 5 8 14 24 72 168 336 1444-1051 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 113.1 262.0 299.5 143.8 1444-1057 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 142.9 249.6 149.3 157.1

TABLE 42 Individual and Mean Plasma Concentrations (ngEq/mL) of P5 using a Radio-Quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 0 0.5 1 2 3 4 5 8 14 24 72 168 336 1444-1042 0.0 0.0 75.0 129.9 150.2 189.8 246.6 173.8 151.8 147.1 0.0 0.0 7.6 1444-1051 0.0 69.2 126.6 144.7 114.6 116.8 106.6 102.2 0.0 0.0 61.8 31.8 0.0 1444-1052 0.0 42.1 76.1 189.6 151.9 144.0 83.4 83.0 84.9 137.1 89.9 0.0 0.0 N 3 3 3 3 3 3 3 3 3 3 3 3 3 Mean 0.0 37.1 92.6 154.7 138.9 150.2 145.5 119.7 78.9 94.7 50.6 10.6 2.5 SD 0.0 34.9 29.5 31.1 21.1 36.9 88.3 47.9 76.1 82.2 46.0 18.4 4.4 SEM 0.0 20.1 17.0 17.9 12.2 21.3 51.0 27.6 43.9 47.5 26.6 10.6 2.5 Min 0.0 0.0 75.0 129.9 114.6 116.8 83.4 83.0 0.0 0.0 0.0 0.0 0.0 Median 0.0 42.1 76.1 144.7 150.2 144.0 106.6 102.2 84.9 137.1 61.8 0.0 0.0 Max 0.0 69.2 126.6 189.6 151.9 189.8 246.6 173.8 151.8 147.1 89.9 31.8 7.6 % CV NA 94 32 20 15 25 61 40 96 87 91 173 173 GM NA NA 89.7 152.7 137.8 147.2 129.9 113.8 NA NA NA NA NA GM: Geometric Mean; NA: Not Applicable Subjects whose PK profile did not contain more than five consecutive data points with a quantifiable concentration value. Time (hours) Subject 0 0.5 1 2 3 4 5 8 14 24 72 168 336 1444-1023 0.0 0.0 0.0 0.0 146.8 0.0 0.0 0.0 0.0 112.5 0.0 37.7 11.4 1444-1040 0.0 0.0 0.0 126.4 145.3 160.8 0.0 0.0 81.0 103.9 0.0 0.0 0.0 1444-1057 0.0 0.0 0.0 123.7 184.7 0.0 131.9 86.6 128.2 98.7 0.0 21.5 0.0

TABLE 43 Individual and Mean Plasma Concentrations (ngEq/mL) of P7 using a Radio-Quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Time (hours) Subject 0 0.5 1 2 3 4 5 8 14 24 72 168 336 1444-1051 0.0 55.4 76.8 95.3 72.7 85.0 57.1 38.4 0.0 0.0 0.0 0.0 0.0 N 1 1 1 1 1 1 1 1 1 1 1 1 1 Mean 0.0 55.4 76.8 95.3 72.7 85.0 57.1 38.4 0.0 0.0 0.0 0.0 0.0 SD NA NA NA NA NA NA NA NA NA NA NA NA NA SEM NA NA NA NA NA NA NA NA NA NA NA NA NA Min 0.0 55.4 76.8 95.3 72.7 85.0 57.1 38.4 0.0 0.0 0.0 0.0 0.0 Median 0.0 55.4 76.8 95.3 72.7 85.0 57.1 38.4 0.0 0.0 0.0 0.0 0.0 Max 0.0 55.4 76.8 95.3 72.7 85.0 57.1 38.4 0.0 0.0 0.0 0.0 0.0 % CV NA NA NA NA NA NA NA NA NA NA NA NA NA GM NA 55.4 76.8 95.3 72.7 85.0 57.1 38.4 NA NA NA NA NA GM: Geometric Mean; NA: Not Applicable Subjects whose PK profile did not contain more than five consecutive data points with a quantifiable concentration value. Time (hours) Subject 0 0.5 1 2 3 4 5 8 14 24 72 168 336 1444-1023 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1444-1040 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1444-1042 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1444-1052 0.0 0.0 0.0 110.5 156.0 0.0 87.1 0.0 0.0 0.0 0.0 0.0 0.0 1444-1057 0.0 0.0 106.9 0.0 0.0 106.2 54.2 56.4 0.0 0.0 0.0 0.0 0.0

TABLE 44 Individual Plasma Concentrations (ngEq/mL) of P2 using a Radio-quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects Subjects whose PK profile did not contain more than five consecutive data points with a quantifiable concentration value. Time (hours) Subject 0 0.5 1 2 3 4 5 8 14 24 72 168 336 1444-1023 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 41.5 0.0 0.0 0.0 1444-1040 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1444-1042 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1444-1051 0.0 0.0 0.0 0.0 0.0 49.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1444-1052 0.0 0.0 58.7 0.0 74.1 0.0 0.0 72.7 0.0 0.0 0.0 0.0 0.0 1444-1057 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 46.3 0.0 0.0 0.0

TABLE 45 Individual and Descriptive Statistics of Plasma Pharmacokinetic Parameters of XL184 using a Radio-quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC_(0-t) AUC₀₋₂₄ AUC₀₋₇₂ Ratio^(b) AUC_(0-inf) k_(el) t_(1/2) Subject (ngEq/mL) (h) (h · ngEq/mL) (h · ngEq/mL) (h · ngEq/mL) (%) (h · ngEq/mL) (1/h) (h) 1444-1023 895 1.98 29900 8890 17400 15.0 31100 0.00876 79.1 1444-1040 1130 2.00 52600 14300 33500 22.5 53700 0.0119 58.0 1444-1042 1490 4.00 53600 15200 37600 20.8 55000 0.0215 32.2 1444-1051 818 1.00 33200 7660 17400 25.1 38000 0.00685 101 1444-1052 1060 3.00 21300 8770 16100 10.2 24000 0.00909 76.2 1444-1057 1080 1.00 37700 9600 20600 26.4 39800 0.00906 76.5 N 6 6 6 6 6 6 6 6 6 Mean 1080 2.16 38100 10700 23800 20.0 40300 0.0112 70.5 SD 234 1.17 12800 3170 9340 6.24 12300 0.0053 23.2 SEM 95.5 0.48 5240 1300 3810 2.55 5010 0.00216 9.48 Min 818 1.00 21300 7660 16100 10.2 24000 0.00685 32.2 Median 1070 1.99 35500 9250 19000 21.7 38900 0.00908 76.4 Max 1490 4.00 53600 15200 37600 26.4 55000 0.0215 101 % CV 22 54 34 30 39 31 30 47 33 GM 1060 1.90 36200 10400 22400 19.0 38700 0.0104 66.6 GM: Geometric Mean; ^(b)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 6 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el) apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution.

TABLE 46 Individual and Descriptive Statistics of Plasma Pharmacokinetic Parameters of XL184-Half-dimer** using a Radio-quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC_(0-t) AUC₀₋₂₄ AUC₀₋₇₂ Ratio^(a) Ratio^(b) AUC_(0-inf) k_(el) t_(1/2) Subject (ngEq/mL) (h) (h · ngEq/mL) (h · ngEq/mL) (h · ngEq/mL) (%) (%) (h · ngEq/mL) (1/h) (h) 1444-1023 174 1.98 6290 2750 6290 21.0 3.15 NR NR NR 1444-1040 85.9 1.00 1550 1550 3360 2.95 0.664 NR NR NR 1444-1042 295 24.03 15200 5000 15200 28.4 5.91 NE NE NE 1444-1051 213 1.00 12900 3370 8020 38.9 9.77 NR NR NR 1444-1052 255 14.00 16400 5050 9160 77.0 7.89 17600 0.00889 77.9 1444-1057 236 1.00 14400 3940 10000 38.2 10.1 15100 0.0184 37.8 N 6 6 6 6 6 6 6 2 2 2 Mean 210 7.17 11100 3610 8680 34.4 6.25 16400 0.0136 57.9 SD 73.0 9.72 5890 1350 3980 24.7 3.76 1770 0.00672 28.4 SEM 29.8 3.97 2400 552 1620 10.1 1.54 1250 0.00476 20.1 Min 85.9 1.00 1550 1550 3360 2.95 0.664 15100 0.00889 37.8 Median 225 1.49 13700 3650 8590 33.3 6.90 16400 0.0136 57.9 Max 295 24.03 16400 5050 15200 77.0 10.1 17600 0.0184 77.9 % CV 35 136 53 37 46 72 60 11 49 49 GM 196 2.96 8760 3360 7870 24.2 4.61 16300 0.0128 54.3 **Co-eluted with Demethyl XL184 glucuronide B; GM: Geometric Mean; ^(a)ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(b)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 6 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution; NE: Not Estimable; NR: Not reportable since AUC_(0-t) /AUC_(0-inf) ratio < 0.80

TABLE 47 Individual and Descriptive Statistics of Plasma Pharmacokinetic Parameters of XL184-N-oxide using a Radio-quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects AUC_(0-t) AUC_(0-inf) C_(max) t_(max) (h · ngEq/ AUC₀₋₂₄ AUC₀₋₇₂ Ratio^(a) Ratio^(b) (h · ngEq/ k_(el) t_(1/2) Subject (ngEq/mL) (h) mL) (h · ngEq/mL) (h · ngEq/mL) (%) (%) mL) (1/h) (h) 1444-1023 233 4.00 13100 3650 8790 43.8 6.55 14100 0.0086 80.6 1444-1040 327 4.00 27900 7050 17000 53.0 12.0 29100 0.00847 81.8 1444-1042 345 3.00 8180 3110 8180 15.3 3.18 NR NR NR 1444-1051 222 2.00 10700 3660 10700 32.2 8.10 NR NR NR 1444-1052 326 3.00 3580 3560 7430 16.8 1.72 NR NR NR 1444-1057 341 2.00 16300 4790 11700 43.2 11.4 19100 0.0122 56.9 N 6 6 6 6 6 6 6 3 3 3 Mean 299 3.00 13300 4300 10600 34.1 7.16 20800 0.00976 73.1 SD 56.0 0.89 8360 1460 3490 15.4 4.20 7640 0.00212 14.0 SEM 22.9 0.37 3410 594 1430 6.30 1.71 4410 0.00122 8.11 Min 222 2.00 3580 3110 7430 15.3 1.72 14100 0.00847 56.9 Median 327 3.00 11900 3650 9750 37.7 7.33 19100 0.0086 80.6 Max 345 4.00 27900 7050 17000 53.0 12.0 29100 0.0122 81.8 % CV 19 30 63 34 33 45 59 37 22 19 GM 294 2.88 11100 4140 10200 30.7 5.84 19900 0.00961 72.1 GM: Geometric Mean; ^(a)ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(b)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 6 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution; NR: Not reportable since AUC_(0-t)/AUC_(0-inf) ratio < 0.80

TABLE 48 Individual and Descriptive Statistics of Plasma Pharmacokinetic Parameters of XL184-Sulfate*** using a Radio-quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects AUC_(0-t) AUC_(0-inf) C_(max) t_(max) (h · ngEq/ AUC₀₋₂₄ AUC₀₋₇₂ Ratio^(a) Ratio^(b) (h · ngEq/ k_(el) t_(1/2) Subject (ngEq/mL) (h) mL) (h · ngEq/mL) (h · ngEq/mL) (%) (%) mL) (1/h) (h) 1444-1023 575 4.00 58100 9980 25900 194 29.1 63800 0.00722 96.0 1444-1040 867 24.03 108000 15700 48200 205 46.3 113000 0.00958 72.3 1444-1042 718 5.00 69300 9370 34500 129 26.9 70500 0.0121 57.2 1444-1051 516 24.08 67600 10200 30100 204 51.2 80000 0.00606 114 1444-1052 542 1.98 41700 10200 28200 196 20.1 43400 0.0103 67.1 1444-1057 674 4.00 74500 12300 32500 198 52.1 76400 0.0101 68.4 N 6 6 6 6 6 6 6 6 6 6 Mean 649 10.52 69900 11300 33200 188 37.6 74500 0.00923 79.2 SD 132 10.53 22000 2360 7940 29.1 13.9 22900 0.00221 21.4 SEM 54.0 4.30 8970 964 3240 11.9 5.67 9330 0.000901 8.73 Min 516 1.98 41700 9370 25900 129 20.1 43400 0.00606 57.2 Median 625 4.50 68500 10200 31300 197 37.7 73500 0.00984 70.4 Max 867 24.08 108000 15700 48200 205 52.1 113000 0.0121 114 % CV 20 100 31 21 24 15 37 31 24 27 GM 638 6.71 67100 11100 32500 185 35.3 71600 0.00899 77.0 ***Co-eluted with Half-dimer methyl ester; GM: Geometric Mean; ^(a)ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(b)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 6 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution;

TABLE 49 Individual and Descriptive Statistics of Plasma Pharmacokinetic Parameters of Demethyl Half-dimer Sulfate using a Radio- quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC_(0-t) AUC₀₋₂₄ AUC₀₋₇₂ Ratio^(a) Ratio^(b) AUC_(0-inf) k_(el) t_(1/2) Subject (ngEq/mL) (h) (h · ngEq/mL) (h · ngEq/mL) (h · ngEq/mL) (%) (%) (h · ngEq/mL) (1/h) (h) 1444-1023 418 24.00 92500 4250 22900 309 46.3 NR NR NR 1444-1040 172 72.00 43300 917 7150 82.3 18.6 NR NR NR 1444-1042 391 168.00 103000 2590 19100 192 40.0 NE NE NE 1444-1052 533 71.98 117000 2320 20300 549 56.3 NR NR NR N 4 4 4 4 4 4 4 0 0 0 Mean 379 84.00 89000 2520 17400 283 40.3 NA NA NA SD 151 60.40 32000 1370 7000 200 15.9 NA NA NA SEM 75.4 30.20 16000 683 3500 100 7.97 NA NA NA Min 172 24.00 43300 917 7150 82.3 18.6 NA NA NA Median 405 71.99 97800 2460 19700 251 43.2 NA NA NA Max 533 168.00 117000 4250 22900 549 56.3 NA NA NA % CV 40 72 36 54 40 71 40 NA NA NA GM 350 67.61 83400 2200 15900 228 37.3 NA NA NA GM: Geometric Mean; NR: Not reportable since AUC_(0-t)/AUC_(0-inf) ratio < 0.80; NE: Not Estimable; NA: Not Applicable; ^(a)ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(b)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 6 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution

TABLE 50 Individual and Descriptive Statistics of Plasma Pharmacokinetic Parameters of P5 using a Radio-quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC_(0-t) AUC₀₋₂₄ AUC₀₋₇₂ Ratio^(a) Ratio^(b) AUC_(0-inf) k_(el) t_(1/2) Subject (ngEq/mL) (h) (h · ngEq/mL) (h · ngEq/mL) (h · ngEq/mL) (%) (%) (h · ngEq/mL) (1/h) (h) 1444-1042 247 5.00 7920 3750 7280 14.8 3.08 8720 0.00945 73.4 1444-1051 145 2.00 7150 1180 2660 21.5 5.41 NR NR NR 1444-1052 190 1.98 7910 2470 7920 37.1 3.80 NR NR NR N 3 3 3 3 3 3 3 1 1 1 Mean 194 2.99 7660 2470 5950 24.5 4.10 8720 0.00945 73.4 SD 51.1 1.74 442 1290 2870 11.4 1.19 NA NA NA SEM 29.5 1.00 255 743 1660 6.61 0.689 NA NA NA Min 145 1.98 7150 1180 2660 14.8 3.08 8720 0.00945 73.4 Median 190 2.00 7910 2470 7280 21.5 3.80 8720 0.00945 73.4 Max 247 5.00 7920 3750 7920 37.1 5.41 8720 0.00945 73.4 % CV 26 58 6 52 48 47 29 NA NA NA GM 189 2.71 7650 2220 5350 22.8 3.99 8720 0.00945 73.4 GM: Geometric Mean; NR: Not reportable since AUC_(0-t)/AUC_(0-inf) ratio < 0.80; NA: Not Applicable; ^(a)ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(b)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 6 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(max), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution

TABLE 51 Individual and Descriptive Statistics of Plasma Pharmacokinetic Parameters of P7 using a Radio-quantitative Method following a Single 175 mg Oral Administration of [¹⁴C]-XL184 (100 μCi) to Healthy Male Subjects C_(max) t_(max) AUC_(0-t) AUC₀₋₂₄ AUC₀₋₇₂ Ratio^(a) Ratio^(b) AUC_(0-inf) k_(el) t_(1/2) Subject (ngEq/mL) (h) (h · ngEq/mL) (h · ngEq/mL) (h · ngEq/mL) (%) (%) (h · ngEq/mL) (1/h) (h) 1444-1051 95.3 2.00 510 625 625 1.54 0.386 NR NR NR N 1 1 1 1 1 1 1 0 0 0 Mean 95.3 2.00 510 625 625 1.54 0.386 NA NA NA SD NA NA NA NA NA NA NA NA NA NA SEM NA NA NA NA NA NA NA NA NA NA Min 95.3 2.00 510 625 625 1.54 0.386 NA NA NA Median 95.3 2.00 510 625 625 1.54 0.386 NA NA NA Max 95.3 2.00 510 625 625 1.54 0.386 NA NA NA % CV NA NA NA NA NA NA NA NA NA NA GM 95.3 2.00 510 625 625 1.54 0.386 NA NA NA GM: Geometric Mean; NR: Not reportable since AUC₀₋₄/AUC_(0-inf) ratio < 0.80; NA: Not Applicable; ^(a)ratio of AUC_(0-t) (metabolite)/AUC_(0-t) (parent); ^(b)ratio of AUC_(0-t) (each analyte)/AUC_(0-t) (parent + 6 measured metabolites); C_(max), maximum observed concentration; T_(max), time of the maximum concentration; AUC_(0-t), area under the concentration-time curve from time zero to the time of the last measurable concentration; AUC₀₋₂₄, area under the concentration-time curve from time zero to 24 hours post XL184 dose; AUC₀₋₇₂, area under the concentration-time curve from time zero to 72 hours post XL184 dose; AUC_(0-inf), area under the concentration-time curve from time zero to infinity; k_(el), apparent terminal elimination rate constant; t_(1/2), apparent terminal elimination half-life; CL/F, apparent total body clearance; V/F, apparent total volume of distribution

Procedure for Preparation of Vehicle for [¹⁴C]-XL184 for Oral Solution: PEG-400/TPGS/Ethanol 85/10/5 w/w/w

Example for 600 g—Scale amounts proportionally for other volumes desired.

-   1. Heat about 600 g of PEG 400 in an oven set at 50° C. -   2. Heat about 100 g of TPGS in an oven set at 50° C. Heat till TPGS     has completely liquefied. -   3. Weigh a 1000 mL glass bottle with cap and record the weight. -   4. Tare the balance. -   5. Weigh 510 g of warm PEG 400 from step 1 into the glass bottle     from step 4. -   6. Tare the balance. -   7. Weigh 60 g of TPGS from step 2 into the bottle from step 6. -   8. Mix the contents of the bottle from step 7 by swirling gently. -   9. Place the bottle from step 8 in an oven set at 50° C. for about     30 minutes, swirl the contents intermittently to ensure that the     solution is homogenous. -   10. Remove the bottle from step 9 from the oven and allow it to cool     to RT. -   11. Place the bottle on the balance and tare the balance. -   12. Weigh 30 g of ethanol into the bottle from step 11, seal the     bottle with the cap, and mix the contents gently till the solution     is homogenous. -   13. Label the bottle as follows:     -   “Vehicle for [¹⁴C(U)]XL184 for Oral Solution”     -   “Store tightly capped at 25° C. to 37° C.”     -   Preparation date and time     -   Use date and time (use within 24 hours of preparation).         Note: The vehicle must be stored between 25° C. and 37° C. The         vehicle, when exposed to temperatures below 25° C. for extended         duration (4-6 hours), might become cloudy due to precipitation         of TPGS. If this happens then the vehicle may be heated to         37° C. to dissolve any precipitate. Handling to the vehicle at         ambient temperature during preparation of the formulation is         permissible.

Procedure for Preparation of Oral Solution of [¹⁴C]-XL184

175 mg/subject (salt basis); 100 μCi/subject; concentration of drug in vehicle is about 8 mg/mL (salt basis)

-   1. Prepare 500 g of vehicle according to instructions; include     cinnamon flavoring (0.1% v/v). -   2. Dispense about 263 mL of vehicle into tared dose prep container     (suggest 500 mL quantity). -   3. Add 2100 mg of unlabeled XL184. -   4. Add approx. 10 mg of labeled XL184. -   5. Dissolve drug in vehicle, according to instructions. -   6. Weigh total amount. -   7. Withdraw two or three aliquots of about 1 g each and determine     radioactivity per unit weight, by LSC and drug potency. -   8. Dispense about 22 mL aliquots for each subject and obtain     accurate weight for each aliquot. -   9. Administer each aliquot to subject.

Dose dispensed to each subject will be accurately determined by multiplying weight of each aliquot in Step 8 with activity determined in Step 7.

REFERENCES

Kurzrock R, Sherman S I, Ball D W, Forastiere A A, Cohen R B, Mehra R, Pfister D G, Cohen E E, Janisch L, Nauling F, Hong D S, Ng C S, Ye L, Gagel R F, Frye J, Müller T, Ratain M J, Salgia R. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011; 29(19):2660-6.

Yakes F M, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011; 10(12):2298-308.

The foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications can be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. 

The invention claimed is:
 1. A liquid pharmaceutical composition for oral administration comprising Cabozantinib (S)-malate and a pharmaceutically acceptable carrier, wherein the carrier comprises from 50% to 95% polyethyleneglycols (w/w), from 1% to 30% d-α-tocopheryl polyethylene glycol succinate (TPGS, w/w), and from 0.5% to 20% ethanol (w/w), wherein the liquid formulation when administered to a plurality of patients as a single dose provides an interpatient or intrapatient exposure variability of less than 30%, wherein exposure is represented by a pharmacokinetic parameter selected from the group consisting of area under the plasma concentration-time curve (AUC_(0-t)), maximum observed concentration (C_(max)), time of maximum concentration (t_(max)), apparent terminal elimination rate constant (k_(el)), and apparent terminal elimination half-life calculated as ln(2)/k_(el)(t_(1/2)).
 2. The liquid pharmaceutical composition of claim 1, wherein the amount of Cabozantinib (S)-malate present in the liquid formulation, ranges from 1 mg to 200 mg.
 3. The liquid pharmaceutical composition of claim 1, wherein the amount of Cabozantinib (S)-malate present in the liquid formulation, ranges from 10 mg to 100 mg.
 4. The liquid pharmaceutical composition of claim 1, wherein the carrier comprises from 80% to 90% polyethyleneglycols (w/w), from 5% to 15% TPGS (w/w), and from 1% to 10% ethanol (w/w).
 5. The liquid pharmaceutical composition of claim 4, including a flavoring agent.
 6. A liquid pharmaceutical composition, comprising Cabozantinib (S)-malate and a pharmaceutically acceptable carrier, wherein the carrier comprises ethanol, d-α-tocopheryl polyethylene glycol succinate (TPGS), polyethyleneglycol, and flavorings; and wherein the liquid formulation when administered to a plurality of patients as a single dose provides an interpatient or intrapatient exposure variability of less than 30%, wherein exposure is represented by a pharmacokinetic parameter selected from the group consisting of area under the plasma concentration-time curve (AUC_(0-t)), maximum observed concentration (C_(max)), time of maximum concentration (t_(max)), apparent terminal elimination rate constant (k_(el)), and apparent terminal elimination half-life calculated as ln(2)/k_(el)(t_(1/2)); and wherein the liquid pharmaceutical composition is as provided in one of the following tables: Theoretical Quantity (mg/unit dose) 20-mg 40-mg 60-mg Ingredient Dose Dose Dose Cabozantinib (S)-malate 25.34 50.68 76.02 Polyethylene glycol 400 (PEG 400) 2,934.88 5,869.77 8,804.65 d-α-tocopheryl polyethylene glycol 345.28 690.56 1,035.84 succinate (TPGS) Ethanol 172.64 345.28 517.92 Flavorings 3.45 6.91 10.36 Total 3,481.60 6,963.19 10,444.79

Ingredient (% w/w) Cabozantinib (S)-malate 0.73 Polyethylene glycol 400 (PEG 400) 84.30 d-α-tocopheryl polyethylene glycol 9.92 succinate (TPGS) Ethanol 4.96 Flavorings 0.10 Total 100

Theoretical Quantity Ingredient (mg/unit dose) Cabozantinib (S)-malate 175.00 Polyethylene glycol 400 (PEG 400) 20,268.53 d-α-tocopheryl polyethylene glycol 2,384.53 succinate (TPGS) Ethanol 1,192.27 Flavorings 23.85 Total 24,044.18

Ingredient Function % w/w Cabozantinib (S)-malate Active Ingredient 0.73 Polyethylene glycol 400 (PEG 400) Solubility Enhancer 84.30 d-α-tocopheryl polyethylene glycol Solubility Enchancer and 9.92 succinate (TPGS) Stabilizer Ethanol Solvent 4.96 Flavoring Taste masking agent 0.10 Total
 100.


7. The liquid pharmaceutical composition of claim 6, wherein the liquid formulation when administered to a plurality of patients as a single dose provides an interpatient or intrapatient exposure variability of less than 10%.
 8. A method of treating locally advanced or metastatic urothelial carcinoma or renal cell carcinoma, comprising administering a patient in need of such treatment, a liquid pharmaceutical composition comprising Cabozantinib (S)-malate and a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier comprises from 50% to 95% polyethyleneglycols (w/w), from 1% to 30% d-α-tocopheryl polyethylene glycol succinate (TPGS, w/w), and from 0.5% to 20% ethanol (w/w); and wherein the liquid formulation when administered to a plurality of patients as a single dose provides an interpatient or intrapatient exposure variability of less than 30%, wherein exposure is represented by a pharmacokinetic parameter selected from the group consisting of area under the plasma concentration-time curve (AUC_(0-t)), maximum observed concentration (C_(max)), time of maximum concentration (t_(max)), apparent terminal elimination rate constant (k_(el)), and apparent terminal elimination half-life calculated as ln(2)/k_(el)(t_(1/2)).
 9. The method of claim 8, wherein the amount of Cabozantinib (S)-malate present in the liquid formulation, ranges from 1 mg to 200 mg.
 10. The method of claim 8, wherein the amount of the Cabozantinib (S)-malate present in the liquid formulation, ranges from 10 mg to 100 mg.
 11. The method of claim 8, wherein the carrier comprises from 80% to 90% polyethyleneglycols (w/w), from 5% to 15% TPGS (w/w), and from 1% to 10% ethanol (w/w).
 12. The method of claim 8, wherein the carrier further includes flavorings.
 13. The method of claim 12, wherein the liquid pharmaceutical composition is as provided in one of the following tables: Theoretical Quantity (mg/unit dose) 20-mg 40-mg 60-mg Ingredient Dose Dose Dose Cabozantinib (S)-malate 25.34 50.68 76.02 Polyethylene glycol 400 (PEG 400) 2,934.88 5,869.77 8,804.65 d-α-tocopheryl polyethylene glycol 345.28 690.56 1,035.84 succinate (TPGS) Ethanol 172.64 345.28 517.92 Flavorings 3.45 6.91 10.36 Total 3,481.60 6,963.19 10,444.79

Ingredient (% w/w) Cabozantinib (S)-malate 0.73 Polyethylene glycol 400 (PEG 400) 84.30 d-α-tocopheryl polyethylene glycol 9.92 succinate (TPGS) Ethanol 4.96 Flavorings 0.10 Total 100

Ingredient Theoretical Quantity (mg/unit dose) Cabozantinib (S)-malate 175.00 Polyethylene glycol 400 (PEG 400) 20,268.53 d-α-tocopheryl polyethylene glycol 2,384.53 succinate (TPGS) Ethanol 1,192.27 Flavorings 23.85 Total 24,044.18

Ingredient Function % w/w Cabozantinib (S)-malate Active Ingredient 0.73 Polyethylene glycol 400 (PEG 400) Solubility Enhancer 84.30 d-α-tocopheryl polyethylene glycol Solubility Enchancer and 9.92 succinate (TPGS) Stabilizer Ethanol Solvent 4.96 Flavoring Taste masking agent 0.10 Total
 100. 